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  • N-acetylcysteine inhibits bacterial lipopeptide-mediated neutrophil transmigration through the choroid plexus in the developing brain
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2020-01-23
    Amin Mottahedin; Sandrine Blondel; Joakim Ek; Anna-Lena Leverin; Pernilla Svedin; Henrik Hagberg; Carina Mallard; Jean-Francois Ghersi-Egea; Nathalie Strazielle

    The etiology of neurological impairments associated with prematurity and other perinatal complications often involves an infectious or pro-inflammatory component. The use of antioxidant molecules have proved useful to protect the neonatal brain from injury. The choroid plexuses-CSF system shapes the central nervous system response to inflammation at the adult stage, but little is known on the neuroimmune interactions that take place at the choroidal blood-CSF barrier during development. We previously described that peripheral administration to neonatal mice of the TLR2 ligand PAM3CSK4 (P3C), a prototypic Gram-positive bacterial lipopeptide, induces the migration of innate immune cells to the CSF. Here we showed in neonatal rats exposed to P3C that the migration of neutrophils into the CSF, which occurred through the choroid plexuses, is abolished following administration of the antioxidant drug N-acetylcysteine. Combining light sheet microscopy imaging of choroid plexus, a differentiated model of the blood-CSF barrier, and multiplex cytokine assays, we showed that the choroidal epithelium responds to the bacterial insult by a specific pattern of cytokine secretion, leading to a selective accumulation of neutrophils in the choroid plexus and to their trafficking into CSF. N-acetylcysteine acted by blocking neutrophil migration across both the endothelium of choroidal stromal vessels and the epithelium forming the blood-CSF barrier, without interfering with neutrophil blood count, neutrophil tropism for choroid plexus, and choroidal chemokine-driven chemotaxis. N-acetylcysteine reduced the injury induced by hypoxia-ischemia in P3C-sensitized neonatal rats. Overall, the data show that a double endothelial and epithelial check point controls the transchoroidal migration of neutrophils into the developing brain. They also point to the efficacy of N-acetylcysteine in reducing the deleterious effects of inflammation-associated perinatal injuries by a previously undescribed mechanism, i.e. the inhibition of innate immune cell migration across the choroid plexuses, without interfering with the systemic inflammatory response to infection.

    更新日期:2020-01-23
  • A robust TDP-43 knock-in mouse model of ALS
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2020-01-21
    Shih-Ling Huang; Lien-Szu Wu; Min Lee; Chin-Wen Chang; Wei-Cheng Cheng; Yu-Sheng Fang; Yun-Ru Chen; Pei-Lin Cheng; Che-Kun James Shen

    Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset degenerative disorder of motor neurons. The diseased spinal cord motor neurons of more than 95% of amyotrophic lateral sclerosis (ALS) patients are characterized by the mis-metabolism of the RNA/DNA-binding protein TDP-43 (ALS-TDP), in particular, the presence of cytosolic aggregates of the protein. Most available mouse models for the basic or translational studies of ALS-TDP are based on transgenic overexpression of the TDP-43 protein. Here, we report the generation and characterization of mouse lines bearing homologous knock-in of fALS-associated mutation A315T and sALS-associated mutation N390D, respectively. Remarkably, the heterozygous TDP-43 (N390D/+) mice but not those heterozygous for the TDP-43 (A315T/+) mice develop a full spectrum of ALS-TDP-like pathologies at the molecular, cellular and behavioral levels. Comparative analysis of the mutant mice and spinal cord motor neurons (MN) derived from their embryonic stem (ES) cells demonstrates that different ALS-associated TDP-43 mutations possess critical ALS-causing capabilities and pathogenic pathways, likely modified by their genetic background and the environmental factors. Mechanistically, we identify aberrant RNA splicing of spinal cord Bcl-2 pre-mRNA and consequent increase of a negative regulator of autophagy, Bcl-2, which correlate with and are caused by a progressive increase of TDP-43, one of the early events associated with ALS-TDP pathogenesis, in the spinal cord of TDP-43 (N390D/+) mice and spinal cord MN derived from their ES cells. The TDP-43 (N390D/+) knock-in mice appear to be an ideal rodent model for basic as well as translational studies of ALS- TDP.

    更新日期:2020-01-22
  • Correction to: Comprehensive gene expression meta-analysis identifies signature genes that distinguish microglia from peripheral monocytes/macrophages in health and glioma
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2020-01-08
    Verena Haage; Marcus Semtner; Ramon Oliveira Vidal; Daniel Perez Hernandez; Winnie W. Pong; Zhihong Chen; Dolores Hambardzumyan; Vincent Magrini; Amy Ly; Jason Walker; Elaine Mardis; Philipp Mertins; Sascha Sauer; Helmut Kettenmann; David H. Gutmann

    The original publication of this article [1] contained 3 minor errors in Figs. 1, 3 and 5. In this correction article the updated figures are published. The figure captions describe the updated information in these figures.

    更新日期:2020-01-08
  • Innate signaling within the central nervous system recruits protective neutrophils
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2020-01-08
    Reza Khorooshi; Joanna Marczynska; Ruthe Storgaard Dieu; Vian Wais; Christian Rønn Hansen; Stephanie Kavan; Mads Thomassen; Mark Burton; Torben Kruse; Gill A. Webster; Trevor Owens

    There is great interest in understanding how the central nervous system (CNS) communicates with the immune system for recruitment of protective responses. Infiltrating phagocytic monocytes and granulocytes are implicated in neuroinflammation in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). To investigate how CNS endogenous signals can be harnessed to promote anti-inflammatory programs, we have used a particulate Toll-like receptor 9 and nucleotide-oligomerization domain 2 bispecific innate ligand (MIS416), to address whether its phagocytosis within the CNS recruits protective myeloid cells. We find that MIS416 injected intrathecally into the cerebrospinal fluid via the cisterna magna induced a local chemokine response that recruited blood-derived monocytes and neutrophils to the CNS. These cells phagocytosed MIS416. The increase in EAE severity normally seen from time of onset did not occur in mice receiving MIS416. This suppression of disease symptoms was dependent on expression of the type I interferon receptor (IFNAR). Transfer of intrathecal MIS416-induced neutrophils suppressed EAE in recipient mice, while monocytes did not transfer protection. MIS416-induced neutrophils showed increased IL-10 expression that was IFNAR1-driven. In contrast to intrathecal administration, intravenous administration of MIS416 led to monocyte but not neutrophil infiltration to the CNS. We thus identify a CNS-intrinsic and -specific phagocytosis-induced recruitment of anti-inflammatory neutrophils that contribute to CNS homeostasis and may have therapeutic potential.

    更新日期:2020-01-08
  • α-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-30
    Nolwen L. Rey; Luc Bousset; Sonia George; Zachary Madaj; Lindsay Meyerdirk; Emily Schulz; Jennifer A. Steiner; Ronald Melki; Patrik Brundin

    Alpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner. However, it is still not known why the same pathological protein targets different cell populations, propagates with different kinetics and leads to a variety of diseases (synucleinopathies) with distinct clinical features. The aggregation of the protein alpha-synuclein yields different conformational polymorphs called strains. These strains exhibit distinct biochemical, physical and structural features they are able to imprint to newly recruited alpha-synuclein. This had led to the view that the clinical heterogeneity observed in synucleinopathies might be due to distinct pathological alpha-synuclein strains. To investigate the pathological effects of alpha-synuclein strains in vivo, we injected five different pure strains we generated de novo (fibrils, ribbons, fibrils-65, fibrils-91, fibrils-110) into the olfactory bulb of wild-type female mice. We demonstrate that they seed and propagate pathology throughout the olfactory network within the brain to different extents. We show strain-dependent inclusions formation in neurites or cell bodies. We detect thioflavin S-positive inclusions indicating the presence of mature amyloid aggregates. In conclusion, alpha-synuclein strains seed the aggregation of their cellular counterparts to different extents and spread differentially within the central nervous system yielding distinct propagation patterns. We provide here the proof-of-concept that the conformation adopted by alpha-synuclein assemblies determines their ability to amplify and propagate in the brain in vivo. Our observations support the view that alpha-synuclein polymorphs may underlie different propagation patterns within human brains.

    更新日期:2019-12-31
  • Synapse alterations precede neuronal damage and storage pathology in a human cerebral organoid model of CLN3-juvenile neuronal ceroid lipofuscinosis
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-30
    Gemma Gomez-Giro; Jonathan Arias-Fuenzalida; Javier Jarazo; Dagmar Zeuschner; Muhammad Ali; Nina Possemis; Silvia Bolognin; Rashi Halder; Christian Jäger; Willemijn F. E. Kuper; Peter M. van Hasselt; Holm Zaehres; Antonio del Sol; Herman van der Putten; Hans R. Schöler; Jens C. Schwamborn

    The juvenile form of neuronal ceroid Lipofuscinosis (JNCL) is the most common form within this group of rare lysosomal storage disorders, causing pediatric neurodegeneration. The genetic disorder, which is caused by recessive mutations affecting the CLN3 gene, features progressive vision loss, cognitive and motor decline and other psychiatric conditions, seizure episodes, leading to premature death. Animal models have traditionally aid the understanding of the disease mechanisms and pathology and are very relevant for biomarker research and therapeutic testing. Nevertheless, there is a need for establishing reliable and predictive human cellular models to study the disease. Since patient material, particularly from children, is scarce and difficult to obtain, we generated an engineered a CLN3-mutant isogenic human induced pluripotent stem cell (hiPSC) line carrying the c.1054C → T pathologic variant, using state of the art CRISPR/Cas9 technology. To prove the suitability of the isogenic pair to model JNCL, we screened for disease-specific phenotypes in non-neuronal two-dimensional cell culture models as well as in cerebral brain organoids. Our data demonstrates that the sole introduction of the pathogenic variant gives rise to classical hallmarks of JNCL in vitro. Additionally, we discovered an alteration of the splicing caused by this particular mutation. Next, we derived cerebral organoids and used them as a neurodevelopmental model to study the particular effects of the CLN3Q352X mutation during brain formation in the disease context. About half of the mutation -carrying cerebral organoids completely failed to develop normally. The other half, which escaped this severe defect were used for the analysis of more subtle alterations. In these escapers, whole-transcriptome analysis demonstrated early disease signatures, affecting pathways related to development, corticogenesis and synapses. Complementary metabolomics analysis confirmed decreased levels of cerebral tissue metabolites, some particularly relevant for synapse formation and neurotransmission, such as gamma-amino butyric acid (GABA). Our data suggests that a mutation in CLN3 severely affects brain development. Furthermore, before disease onset, disease -associated neurodevelopmental changes, particular concerning synapse formation and function, occur.

    更新日期:2019-12-31
  • Brain tumor with an ATXN1-NUTM1 fusion gene expands the histologic spectrum of NUTM1-rearranged neoplasia
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-30
    Aurore Siegfried; Julien Masliah-Planchon; Franck-Emmanuel Roux; Delphine Larrieu-Ciron; Gaelle Pierron; Yvan Nicaise; Marion Gambart; Isabelle Catalaa; Sarah Péricart; Charlotte Dubucs; Badreddine Mohand-Oumoussa; Franck Tirode; Franck Bourdeaut; Emmanuelle Uro-Coste

    We report a novel ATXN1-NUTM1 gene fusion in a primitive brain tumor (Fig 1a). A 21-year-old woman was seen in an emergency department for symptoms of increased intracranial pressure, visual disturbance and right hemiparesis. She reported unusual headaches for the past 3 weeks. MRI showed a frontal tumor with intratumoral hemorrhage (Fig. 1b). The entire tumor was surgically removed. The patient did not receive any additional treatment. 16 months after surgery, the patient was symptom-free and MRI showed no recurrence of the tumor. Fig. 1 ATXN1-NUTM1 gene fusion, confirmed by RT-PCR and Sanger sequencing (a). MRI identified a frontal mass. Enhancement after contrast injection (T1) (b). Representative histopathology. On the left, loose area with neuron-like tumor cells (*detail). On the right, increase in cell density (c). Fascicular architecture with three mitoses (arrows) (d). Chondroid-like, myxoid and hyalinized areas were observed (e). Undifferentiated cells with large nucleoli in a chondromyxoid background (f). Strong GFAP staining was observed. Tumor showed vascular proliferation (g). Neurofilament staining circumscribed the tumor mass with no significant staining within the tumor (h). p53 accumulated in tumor nuclei (i). Anti-NUT antibody staining showing homogeneous intranuclear expression (j)Full size image Histological features were characterized by a fascicular architectural pattern and chondro-myxoid areas (Fig. 1c, d, e, f). Neuron-like tumor cells were apparent (Fig. 1c). Mitotic activity was overall low but increased in some foci (Fig. 1d). Strong GFAP staining led to an initial diagnosis of an unclassified glioneuronal tumor in spite of olig2 and PS100 negativity (Fig. 1g). Microscopically, the tumor was well circumscribed (Fig. 1h). p53 was accumulated (Fig. 1i). CD56 was strongly expressed. TTF1, chromogranin, synaptophysin, CD34, p63, CK5/6 and smooth muscle actin were negative. ATRX, INI1 and BRG1 expression was maintained. Using the Heidelberg DNA methylation-based CNS tumor classifier, no class prediction was obtained with a greater than ≥0.9 confidence threshold [1]. The closest entity was the CNS Ewing Family Tumor CIC group with a score of 0.235 (Additional file 1: Table S1) (Case methylation data: http://www.ncbi.nlm.nih.gov/geo; GSE138550). This tumor group is associated to the CIC-NUTM1 gene fusion [6]. We observed strong homogeneous nuclear staining with an anti-NUT antibody, suggesting the presence of a CIC-NUTM1 fusion (Fig. 1j). RNA sequencing using the Illumina TruSight RNA Fusion panel and Manta for fusion calling revealed a novel ATXN1-NUTM1 fusion. A CIC-NUTM1 fusion was not detected. ETV4 was overexpressed as in CIC-fused sarcomas [4, 6]. No pathogenic variants were observed in tumor DNA using a 571-gene targeted sequencing panel (Additional file 2: Table S2). The fusion gene transcript encompassed almost all of the ATXN1 coding sequence and the entire exon 6, 7 and 8 regions of NUTM1. The most common NUTM1 breakpoints map between exon 1 and 2, but breakpoints at the distal end of exon 5 have also been described in some CIC-NUTM1 sarcomas [4]. Initially associated with NUT midline carcinomas, NUTM1 fusions have now been described in a broad spectrum of tumors ranging from carcinoma to sarcoma and leukemia [2, 3, 7]. The most common fusion partner gene in carcinoma and sarcoma is BRD4 followed by BRD3 and NSD3. Various new partners have been recently described [2, 3, 5]. The prognosis of these tumors is generally poor, although NUT-associated leukemias appear to be associated with a better prognosis and YAP1-NUTM1 is associated with benign skin adnexal gland tumors [3, 5]. CIC rearranged sarcomas are often fused to DUX4 and less frequently to NUTM1 [4, 7]. All CIC re-arranged tumors irrespective of their location or their fusion partner gene share the same transcriptomic profile defining a molecular subgroup distinct from NUT carcinoma [4, 7]. Interestingly, ATXN1 codes for ataxin1 which forms a transcriptional repressor complex with CIC. They are both part of the CIC-ATXN1-ATXN1L mitotic cell cycle regulator axis [8]. Excluding CIC-NUTM1 fused tumors, only one NUTM1 rearranged brain tumor has been previously reported, namely a cytokeratin negative BRD4-NUTM1 PNET-like parietal lobe tumor in a 3-year old boy with GFAP and synaptophysin positivity. On methylation profiling, this neoplasm did not cluster with tumors of the CNS Ewing Family Tumor CIC group [2]. Myxoid and chondroid differentiation has been reported in NUTM1-rearranged sarcomas but is unusual in primary glioneuronal tumors. Whether the strong GFAP positivity of our specific case is indicative of a glial tumor or of a sarcoma with myoepithelial differentiation cannot be assessed due to the lack of positive staining and specificity for other markers tested. GFAP positivity has been described in 3 out of 4 NUTM1 rearranged soft tissue or visceral sarcomas, this is in contrast to the CNS Ewing Family Tumor CIC group which fails to express any differentiation markers [2, 6]. We recommend performing NUT immunohistochemistry followed by RNA sequencing to identify any potential NUTM1 fusion partner genes in GFAP+/olig2- unclassified glioma, particularly those with myxoid and/or chondroid features. The ATXN1-NUTM1 fusion gene may define a novel group of rare primary brain tumors. The prognostic influence of NUTM1 fusion partners and the brain localization of NUTM1-rearranged tumors warrant further investigation. 1. Capper D, Jones DTW, Sill M et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474 CAS Article Google Scholar 2. Dickson BC, Sung YS, Rosenblum MK, Reuter VE, Harb M, Wunder JS, Swanson D, Antonescu CR (2018) NUTM1 gene fusions characterize a subset of undifferentiated soft tissue and visceral tumors. Am J Surg Pathol 42:636–645 Article Google Scholar 3. Hormann FM, Hoogkamer AQ, Beverloo HB et al. (2019) NUTM1 is a recurrent fusion gene partner in B cell precursor acute lymphoblastic leukemia associated with increased expression of genes on chromosome band 10p12.31–12.2. Haematologica. [ahead of print] PubMed PMID: 30872366 4. Le Loarer F, Pissaloux D, Watson S et al (2019) Clinicopathologic features of CIC-NUTM1 sarcomas, a new molecular variant of the family of CIC-fused sarcomas. Am J Surg Pathol 43:268–276 Article Google Scholar 5. Sekine S, Kiyono T, Ryo E et al (2019) Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma. J Clin Invest 130:3827–3832 Article Google Scholar 6. Sturm D, Orr BA, Toprak UH et al (2016) New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell. 164:1060–1072 CAS Article Google Scholar 7. Watson S, Perrin V, Guillemot D et al (2018) Transcriptomic definition of molecular subgroups of small round cell sarcomas. J Pathol 245:29–40 CAS Article Google Scholar 8. Wong D, Lounsbury K, Lum A et al (2019) Transcriptomic analysis of CIC and ATXN1L reveal a functional relationship exploited by cancer. Oncogene 38:273–290 CAS Article Google Scholar Download references Samples were obtained from the CHU de Toulouse tumor bank BB-0033-00014. We thank the “Société Française des Cancers de l’Enfant” for their support. Affiliations Departments of Pathology, Neurology, Neurosurgery, Radiology and Pediatric Oncology, Toulouse University Hospital, Toulouse, France Aurore Siegfried , Franck-Emmanuel Roux , Delphine Larrieu-Ciron , Marion Gambart , Isabelle Catalaa , Sarah Péricart , Charlotte Dubucs  & Emmanuelle Uro-Coste INSERM U1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France Aurore Siegfried , Yvan Nicaise  & Emmanuelle Uro-Coste Departments of Genetics and of Oncopediatry and Young Adults, Curie Institute, Paris, France Julien Masliah-Planchon  & Franck Bourdeaut INSERM U830, Laboratory of Translational Research in Pediatric Oncology, SIREDO pediatric oncology center, Curie Institute, Paris, France Julien Masliah-Planchon  & Franck Bourdeaut Department of Somatic Genetics, Curie Institute, Paris, France Gaelle Pierron Plateforme Post-génomique P3S, Faculté de Médecine Pierre et Marie Curie, Paris, France Badreddine Mohand-Oumoussa INSERM 1052, CNRS 5286, Cancer Research Center of Lyon, Centre Léon Bérard, Claude Bernard Lyon 1 University, Lyon, France Franck TirodeAuthors Search for Aurore Siegfried in: PubMed • Google Scholar Search for Julien Masliah-Planchon in: PubMed • Google Scholar Search for Franck-Emmanuel Roux in: PubMed • Google Scholar Search for Delphine Larrieu-Ciron in: PubMed • Google Scholar Search for Gaelle Pierron in: PubMed • Google Scholar Search for Yvan Nicaise in: PubMed • Google Scholar Search for Marion Gambart in: PubMed • Google Scholar Search for Isabelle Catalaa in: PubMed • Google Scholar Search for Sarah Péricart in: PubMed • Google Scholar Search for Charlotte Dubucs in: PubMed • Google Scholar Search for Badreddine Mohand-Oumoussa in: PubMed • Google Scholar Search for Franck Tirode in: PubMed • Google Scholar Search for Franck Bourdeaut in: PubMed • Google Scholar Search for Emmanuelle Uro-Coste in: PubMed • Google Scholar Contributions AS, FT, FB, EUC were major contributors in writing the manuscript. JMP, GP, YN, BMO carried out the molecular genetic studies. AS, SP, EUC characterized the histological features. YN, CD carried out the sequence alignment. FER, DLC, MG, IC contributed to the data collection. All authors read and approved the final manuscript. Corresponding author Correspondence to Emmanuelle Uro-Coste. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Additional file 1: Table S1. Results of the Heidelberg DNA methylation-based CNS tumor classifier (entities and scores). Additional file 2: Table S2. List of the 517 childhood cancer genes in the dragon targeted gene sequencing panel (Illumina_TruSeq Custom Amplicon). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Siegfried, A., Masliah-Planchon, J., Roux, F. et al. Brain tumor with an ATXN1-NUTM1 fusion gene expands the histologic spectrum of NUTM1-rearranged neoplasia. acta neuropathol commun 7, 220 (2019) doi:10.1186/s40478-019-0870-8 Download citation Received 11 December 2019 Accepted 11 December 2019 Published 30 December 2019 DOI https://doi.org/10.1186/s40478-019-0870-8 Keywords NUTM1 ATXN1 NUTM1-rearranged neoplasia RNA sequencing DNA methylation-based classification Central nervous system Oncogenic gene fusions, CIC-ATXN1-ATXN1L axis

    更新日期:2019-12-30
  • Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-23
    Andrew E. Arrant; Jonathan R. Roth; Nicholas R. Boyle; Shreya N. Kashyap; Madelyn Q. Hoffmann; Charles F. Murchison; Eliana Marisa Ramos; Alissa L. Nana; Salvatore Spina; Lea T. Grinberg; Bruce L. Miller; William W. Seeley; Erik D. Roberson

    Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn−/− mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing.

    更新日期:2019-12-25
  • Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-23
    Diego Perez-Rodriguez; Maria Kalyva; Melissa Leija-Salazar; Tammaryn Lashley; Maxime Tarabichi; Viorica Chelban; Steve Gentleman; Lucia Schottlaender; Hannah Franklin; George Vasmatzis; Henry Houlden; Anthony H. V. Schapira; Thomas T. Warner; Janice L. Holton; Zane Jaunmuktane; Christos Proukakis

    Synucleinopathies are mostly sporadic neurodegenerative disorders of partly unexplained aetiology, and include Parkinson’s disease (PD) and multiple system atrophy (MSA). We have further investigated our recent finding of somatic SNCA (α-synuclein) copy number variants (CNVs, specifically gains) in synucleinopathies, using Fluorescent in-situ Hybridisation for SNCA, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism levels for SNCA gains were higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. In MSA substantia nigra (SN), we noted SNCA gains in > 3% of dopaminergic (DA) neurons (identified by neuromelanin) and neuromelanin-negative cells, including olig2-positive oligodendroglia. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: DA neurons in Lewy-body cases, and other cells in the striatonigral degeneration-dominant MSA variant (MSA-SND). Higher mosaicism levels in SN neuromelanin-negative cells may correlate with younger onset in typical MSA-SND, and in cingulate neurons with younger death in PD. Larger sample sizes will, however, be required to confirm these putative findings. We obtained genome-wide somatic CNV profiles from 169 cells from the substantia nigra of two MSA cases, and pons and putamen of one. These showed somatic CNVs in ~ 30% of cells, with clonality and origins in segmental duplications for some. CNVs had distinct profiles based on cell type, with neurons having a mix of gains and losses, and other cells having almost exclusively gains, although control data sets will be required to determine possible disease relevance. We propose that somatic SNCA CNVs may contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs in MSA brain merit further study.

    更新日期:2019-12-25
  • Sleep deprivation of rats increases postsurgical expression and activity of L-type calcium channel in the dorsal root ganglion and slows recovery from postsurgical pain
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-23
    Qi Li; Zi-yu Zhu; Jian Lu; Yu-Chieh Chao; Xiao-xin Zhou; Ying Huang; Xue-mei Chen; Dian-san Su; Wei-feng Yu; Xi-yao Gu

    Perioperative sleep disturbance is a risk factor for persistent pain after surgery. Clinical studies have shown that patients with insufficient sleep before and after surgery experience more intense and long-lasting postoperative pain. We hypothesize that sleep deprivation alters L-type calcium channels in the dorsal root ganglia (DRG), thus delaying the recovery from post-surgical pain. To verify this hypothesis, and to identify new predictors and therapeutic targets for persistent postoperative pain, we first established a model of postsurgical pain with perioperative sleep deprivation (SD) by administering hind paw plantar incision to sleep deprivation rats. Then we conducted behavioral tests, including tests with von Frey filaments and a laser heat test, to verify sensory pain, measured the expression of L-type calcium channels using western blotting and immunofluorescence of dorsal root ganglia (an important neural target for peripheral nociception), and examined the activity of L-type calcium channels and neuron excitability using electrophysiological measurements. We validated the findings by performing intraperitoneal injections of calcium channel blockers and microinjections of dorsal root ganglion cells with adeno-associated virus. We found that short-term sleep deprivation before and after surgery increased expression and activity of L-type calcium channels in the lumbar dorsal root ganglia, and delayed recovery from postsurgical pain. Blocking these channels reduced impact of sleep deprivation. We conclude that the increased expression and activity of L-type calcium channels is associated with the sleep deprivation-mediated prolongation of postoperative pain. L-type calcium channels are thus a potential target for management of postoperative pain.

    更新日期:2019-12-23
  • Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-20
    Raphael Hesse; Maica Llavero Hurtado; Rosemary J. Jackson; Samantha L. Eaton; Abigail G. Herrmann; Marti Colom-Cadena; Makis Tzioras; Declan King; Jamie Rose; Jane Tulloch; Chris-Anne McKenzie; Colin Smith; Christopher M. Henstridge; Douglas Lamont; Thomas M. Wishart; Tara L. Spires-Jones

    Degeneration of synapses in Alzheimer’s disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to disease pathophysiology. We recently observed that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 (APOE4), is associated with exacerbated synapse loss and synaptic accumulation of oligomeric amyloid beta in human AD brain. To begin to understand the molecular cascades involved in synapse loss in AD and how this is mediated by APOE, and to generate a resource of knowledge of changes in the synaptic proteome in AD, we conducted a proteomic screen and systematic in silico analysis of synaptoneurosome preparations from temporal and occipital cortices of human AD and control subjects with known APOE gene status. We examined brain tissue from 33 subjects (7–10 per group). We pooled tissue from all subjects in each group for unbiased proteomic analyses followed by validation with individual case samples. Our analysis identified over 5500 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-associated changes in multiple molecular pathways including a decreased abundance in AD of proteins important for synaptic and mitochondrial function and an increased abundance of proteins involved in neuroimmune interactions and intracellular signaling.

    更新日期:2019-12-21
  • Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer’s disease and aged brains: increased levels correlate with neuropathology
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-21
    Anarmaa Mendsaikhan; Ikuo Tooyama; Jean-Pierre Bellier; Geidy E. Serrano; Lucia I. Sue; Lih-Fen Lue; Thomas G. Beach; Douglas G. Walker

    Progranulin (PGRN) is a protein encoded by the GRN gene with multiple identified functions including as a neurotrophic factor, tumorigenic growth factor, anti-inflammatory cytokine and regulator of lysosomal function. A single mutation in the human GRN gene resulting in reduced PGRN expression causes types of frontotemporal lobar degeneration resulting in frontotemporal dementia. Prosaposin (PSAP) is also a multifunctional neuroprotective secreted protein and regulator of lysosomal function. Interactions of PGRN and PSAP affect their functional properties. Their roles in Alzheimer’s disease (AD), the leading cause of dementia, have not been defined. In this report, we examined in detail the cellular expression of PGRN in middle temporal gyrus samples of a series of human brain cases (n = 45) staged for increasing plaque pathology. Immunohistochemistry showed PGRN expression in cortical neurons, microglia, cerebral vessels and amyloid beta (Aβ) plaques, while PSAP expression was mainly detected in neurons and Aβ plaques, and to a limited extent in astrocytes. We showed that there were increased levels of PGRN protein in AD cases and corresponding increased levels of PSAP. Levels of PGRN and PSAP protein positively correlated with amyloid beta (Aβ), with PGRN levels correlating with phosphorylated tau (serine 205) levels in these samples. Although PGRN colocalized with lysosomal-associated membrane protein-1 in neurons, most PGRN associated with Aβ plaques did not. Aβ plaques with PGRN and PSAP deposits were identified in the low plaque non-demented cases suggesting this was an early event in plaque formation. We did not observe PGRN-positive neurofibrillary tangles. Co-immunoprecipitation studies of PGRN from brain samples identified only PSAP associated with PGRN, not sortilin or other known PGRN-binding proteins, under conditions used. Most PGRN associated with Aβ plaques were immunoreactive for PSAP showing a high degree of colocalization of these proteins that did not change between disease groups. As PGRN supplementation has been considered as a therapeutic approach for AD, the possible involvement of PGRN and PSAP interactions in AD pathology needs to be further considered.

    更新日期:2019-12-21
  • Triiodothyronine modulates neuronal plasticity mechanisms to enhance functional outcome after stroke
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-21
    Daniela Talhada; Joana Feiteiro; Ana Raquel Costa; Tiago Talhada; Elisa Cairrão; Tadeusz Wieloch; Elisabet Englund; Cecília Reis Santos; Isabel Gonçalves; Karsten Ruscher

    The development of new therapeutic approaches for stroke patients requires a detailed understanding of the mechanisms that enhance recovery of lost neurological functions. The efficacy to enhance homeostatic mechanisms during the first weeks after stroke will influence functional outcome. Thyroid hormones (TH) are essential regulators of neuronal plasticity, however, their role in recovery related mechanisms of neuronal plasticity after stroke remains unknown. This study addresses important findings of 3,5,3′-triiodo-L-thyronine (T3) in the regulation of homeostatic mechanisms that adjust excitability – inhibition ratio in the post-ischemic brain. This is valid during the first 2 weeks after experimental stroke induced by photothrombosis (PT) and in cultured neurons subjected to an in vitro model of acute cerebral ischemia. In the human post-stroke brain, we assessed the expression pattern of TH receptors (TR) protein levels, important for mediating T3 actions. Our results show that T3 modulates several plasticity mechanisms that may operate on different temporal and spatial scales as compensatory mechanisms to assure appropriate synaptic neurotransmission. We have shown in vivo that long-term administration of T3 after PT significantly (1) enhances lost sensorimotor function; (2) increases levels of synaptotagmin 1&2 and levels of the post-synaptic GluR2 subunit in AMPA receptors in the peri-infarct area; (3) increases dendritic spine density in the peri-infarct and contralateral region and (4) decreases tonic GABAergic signaling in the peri-infarct area by a reduced number of parvalbumin+ / c-fos+ neurons and glutamic acid decarboxylase 65/67 levels. In addition, we have shown that T3 modulates in vitro neuron membrane properties with the balance of inward glutamate ligand-gated channels currents and decreases synaptotagmin levels in conditions of deprived oxygen and glucose. Interestingly, we found increased levels of TRβ1 in the infarct core of post-mortem human stroke patients, which mediate T3 actions. Summarizing, our data identify T3 as a potential key therapeutic agent to enhance recovery of lost neurological functions after ischemic stroke.

    更新日期:2019-12-21
  • Polarizing receptor activation dissociates fibroblast growth factor 2 mediated inhibition of myelination from its neuroprotective potential
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-19
    Katja Thümmler; Eran Rom; Thomas Zeis; Maren Lindner; Sarah Brunner; John J. Cole; Diana Arseni; Steve Mücklisch; Julia M. Edgar; Nicole Schaeren-Wiemers; Avner Yayon; Christopher Linington

    Fibroblast growth factor (FGF) signaling contributes to failure of remyelination in multiple sclerosis, but targeting this therapeutically is complicated by its functional pleiotropy. We now identify FGF2 as a factor up-regulated by astrocytes in active inflammatory lesions that disrupts myelination via FGF receptor 2 (FGFR2) mediated activation of Wingless (Wnt) signaling; pharmacological inhibition of Wnt being sufficient to abrogate inhibition of myelination by FGF2 in tissue culture. Using a novel FGFR1-selective agonist (F2 V2) generated by deleting the N-terminal 26 amino acids of FGF2 we demonstrate polarizing signal transduction to favor FGFR1 abrogates FGF mediated inhibition of myelination but retains its ability to induce expression of pro-myelinating and immunomodulatory factors that include Cd93, Lif, Il11, Hbegf, Cxcl1 and Timp1. Our data provide new insights into the mechanistic basis of remyelination failure in MS and identify selective activation of FGFR1 as a novel strategy to induce a neuroprotective signaling environment in multiple sclerosis and other neurological diseases.

    更新日期:2019-12-20
  • Organotypic slice culture model demonstrates inter-neuronal spreading of alpha-synuclein aggregates
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-19
    Sara Elfarrash; Nanna Møller Jensen; Nelson Ferreira; Cristine Betzer; Jervis Vermal Thevathasan; Robin Diekmann; Mohamed Adel; Nisreen Mansour Omar; Mohamed Z. Boraie; Sabry Gad; Jonas Ries; Deniz Kirik; Sadegh Nabavi; Poul Henning Jensen

    Here we describe the use of an organotypic hippocampal slice model for studying α-synuclein aggregation and inter-neuronal spreading initiated by microinjection of pre-formed α-synuclein fibrils (PFFs). PFF injection at dentate gyrus (DG) templates the formation of endogenous α-synuclein aggregates in axons and cell bodies of this region that spread to CA3 and CA1 regions. Aggregates are insoluble and phosphorylated at serine-129, recapitulating Lewy pathology features found in Parkinson’s disease and other synucleinopathies. The model was found to favor anterograde spreading of the aggregates. Furthermore, it allowed development of slices expressing only serine-129 phosphorylation-deficient human α-synuclein (S129G) using an adeno-associated viral (AAV) vector in α-synuclein knockout slices. The processes of aggregation and spreading of α-synuclein were thereby shown to be independent of phosphorylation at serine-129. We provide methods and highlight crucial steps for PFF microinjection and characterization of aggregate formation and spreading. Slices derived from genetically engineered mice or manipulated using viral vectors allow testing of hypotheses on mechanisms involved in the formation of α-synuclein aggregates and their prion-like spreading.

    更新日期:2019-12-20
  • Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-18
    Hormos Salimi Dafsari; Nur Mehpare Kocaturk; Hülya-Sevcan Daimagüler; Anna Brunn; Jörg Dötsch; Joachim Weis; Martina Deckert; Sebahattin Cirak

    Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower’s sign, and skeletal muscle biopsy revealed myopathic changes with core-like structures. Whole exome sequencing of this index patient lead to the discovery of a novel genetically defined CM subtype based on bi-allelic mutations in the uncoordinated mutant number-45 myosin chaperone B (UNC45B) NM_173167:c.2261G > A, p.Arg754Gln. The mutation is conserved in evolution and co-segregates within the pedigree with the phenotype, and located in the myosin binding armadillo repeat domain 3 (ARM3), and has a CADD Score of 35. On a multimeric level, UNC45B aggregates to a chain which serves as an assembly line and functions as a “template” defining the geometry, regularity, and periodicity of myosin arranged into muscle thick filaments. Our discovery is in line with the previously described myopathological phenotypes in C. elegans and in vertebrate mutants and knockdown–models. In conclusion, we here report for the first time a patient with an UNC45B mutation causing a novel genetically defined congenital myopathy disease entity.

    更新日期:2019-12-19
  • Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-16
    Margarita Chumarina; Kaspar Russ; Carla Azevedo; Andreas Heuer; Maria Pihl; Anna Collin; Eleonor Åsander Frostner; Eskil Elmer; Poul Hyttel; Graziella Cappelletti; Michela Zini; Stefano Goldwurm; Laurent Roybon

    Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson’s disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1Q811R) variant midbrain dopaminergic neuron-containing spheroids (MDNS) from a female patient who developed early-onset PD, and compared them to cultures derived from a healthy control of the same gender. Both POLG1 variant and control MDNS contained functional midbrain regionalized TH/FOXA2-positive dopaminergic neurons, capable of releasing dopamine. Western blot analysis identified the presence of high molecular weight oligomeric alpha-synuclein in POLG1Q811R MDNS compared to control cultures. In order to assess POLG1Q811R-related cellular alterations within the MDNS, we applied mass-spectrometry based quantitative proteomic analysis. In total, 6749 proteins were identified, with 61 significantly differentially expressed between POLG1Q811R and control samples. Pro- and anti-inflammatory signaling and pathways involved in energy metabolism were altered. Notably, increased glycolysis in POLG1Q811R MDNS was suggested by the increase in PFKM and LDHA levels and confirmed using functional analysis of glycolytic rate and oxygen consumption levels. Our results validate the use of iPSCs to assess cellular alterations in relation to PD pathogenesis, in a unique PD patient carrying a novel p.Q811R variation in POLG1, and identify several altered pathways that may be relevant to PD pathogenesis.

    更新日期:2019-12-17
  • Glycine-alanine dipeptide repeats spread rapidly in a repeat length- and age-dependent manner in the fly brain
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-16
    Javier Morón-Oset; Tessa Supèr; Jacqueline Esser; Adrian M. Isaacs; Sebastian Grönke; Linda Partridge

    Hexanucleotide repeat expansions of variable size in C9orf72 are the most prevalent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense transcripts of the expansions are translated by repeat-associated non-AUG translation into five dipeptide repeat proteins (DPRs). Of these, the polyGR, polyPR and, to a lesser extent, polyGA DPRs are neurotoxic, with polyGA the most abundantly detected DPR in patient tissue. Trans-cellular transmission of protein aggregates has recently emerged as a major driver of toxicity in various neurodegenerative diseases. In vitro evidence suggests that the C9 DPRs can spread. However, whether this phenomenon occurs under more complex in vivo conditions remains unexplored. Here, we used the adult fly brain to investigate whether the C9 DPRs can spread in vivo upon expression in a subset of neurons. We found that only polyGA can progressively spread throughout the brain, which accumulates in the shape of aggregate-like puncta inside recipient cells. Interestingly, GA transmission occurred as early as 3 days after expression induction. By comparing the spread of 36, 100 and 200 polyGA repeats, we found that polyGA spread is enhanced upon expression of longer GA DPRs. Transmission of polyGA is greater in older flies, indicating that age-associated factors exacerbate the spread. These data highlight a unique propensity of polyGA to spread throughout the brain, which could contribute to the greater abundance of polyGA in patient tissue. In addition, we present a model of early GA transmission that is suitable for genetic screens to identify mechanisms of spread and its consequences in vivo.

    更新日期:2019-12-17
  • Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-16
    Libin Zhou; Joseph Flores; Anastasia Noël; Olivier Beauchet; P. Jesper Sjöström; Andrea C. LeBlanc

    Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal CA1 neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (MB), a phenothiazine that inhibits caspases, alters Caspase-6-induced neurodegeneration and cognitive impairment in mice. Aged cognitively impaired Casp6-overexpressing mice were treated with methylene blue in drinking water for 1 month. Methylene blue treatment did not alter Caspase-6 levels, assessed by RT-PCR, western blot and immunohistochemistry, but inhibited fluorescently-labelled Caspase-6 activity in acute brain slice intact neurons. Methylene blue treatment rescued Caspase-6-induced episodic and spatial memory deficits measured by novel object recognition and Barnes maze, respectively. Methylene blue improved synaptic function of hippocampal CA1 neurons since theta-burst long-term potentiation (LTP), measured by field excitatory postsynaptic potentials (fEPSPs) in acute brain slices, was successfully induced in the Schaffer collateral-CA1 pathway in methylene blue-treated, but not in vehicle-treated, Caspase-6 mice. Increased neuroinflammation, measured by ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia numbers and subtypes, and glial fibrillary acidic protein (GFAP)-positive astrocytes, were decreased by methylene blue treatment. Therefore, methylene blue reverses Caspase-6-induced cognitive deficits by inhibiting Caspase-6, and Caspase-6-mediated neurodegeneration and neuroinflammation. Our results indicate that Caspase-6-mediated damage is reversible months after the onset of cognitive deficits and suggest that methylene blue could benefit Alzheimer disease patients by reversing Caspase-6-mediated cognitive decline.

    更新日期:2019-12-17
  • Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-12
    Amit U. Joshi; Lauren D. Van Wassenhove; Kelsey R. Logas; Paras S. Minhas; Katrin I. Andreasson; Kenneth I. Weinberg; Che-Hong Chen; Daria Mochly-Rosen

    Aldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

    更新日期:2019-12-13
  • Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-12
    Christy M. Kelley; Sylvia E. Perez; Elliott J. Mufson

    Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropathological diagnosis defined as stage II, III, or IV. Sections were immunolabeled using an early (AT8) or a late (TauC3) marker for pathological tau and for amyloid beta (Aβ) species (6E10, Aβ1–42 and thioflavin S). Stereological analysis revealed that stage III had significantly less AT8-positive neurons and dystrophic neurites than stage IV in all MTL regions except hippocampal subfield CA3, whereas significantly more AT8-positive neurons, dystrophic neurites, and neurite clusters were found in the perirhinal cortex, entorhinal cortex, hippocampal CA1, and subiculum of CTE stage III compared with stage II. TauC3-positive pathology was significantly higher in the perirhinal and subicular cortex of stage IV compared to stage III and the perirhinal cortex of stage III compared to stage II. AT8-positive neurite clusters were observed in stages III and IV, but virtually absent in stage II. When observed, Aβ pathology appeared as amyloid precursor protein (APP)/Aβ (6E10)-positive diffuse plaques independent of region. Thioflavine S labeling, did not reveal evidence for fibril or neuritic pathology associated with plaques, confirming a diffuse, non-cored plaque phenotype in CTE. Total number of AT8-positive profiles correlated with age at death, age at symptom onset, and time from retirement to death. There was no association between AT8-positive tau pathology and age sport began, years played, or retirement age, and no difference between CTE stage and the highest level of sport played. In summary, our findings demonstrate different tau profiles in the MTL across CTE stages, proffering CA3 tau pathology and MTL dystrophic neurite clusters as possible markers for the transition between early (II) and late (III/IV) stages, while highlighting CTE as a progressive noncommunicative tauopathy.

    更新日期:2019-12-13
  • Molecular signature of different lesion types in the brain white matter of patients with progressive multiple sclerosis
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-11
    Maria L. Elkjaer; Tobias Frisch; Richard Reynolds; Tim Kacprowski; Mark Burton; Torben A. Kruse; Mads Thomassen; Jan Baumbach; Zsolt Illes

    To identify pathogenetic markers and potential drivers of different lesion types in the white matter (WM) of patients with progressive multiple sclerosis (PMS), we sequenced RNA from 73 different WM areas. Compared to 25 WM controls, 6713 out of 18,609 genes were significantly differentially expressed in MS tissues (FDR < 0.05). A computational systems medicine analysis was performed to describe the MS lesion endophenotypes. The cellular source of specific molecules was examined by RNAscope, immunohistochemistry, and immunofluorescence. To examine common lesion specific mechanisms, we performed de novo network enrichment based on shared differentially expressed genes (DEGs), and found TGFβ-R2 as a central hub. RNAscope revealed astrocytes as the cellular source of TGFβ-R2 in remyelinating lesions. Since lesion-specific unique DEGs were more common than shared signatures, we examined lesion-specific pathways and de novo networks enriched with unique DEGs. Such network analysis indicated classic inflammatory responses in active lesions; catabolic and heat shock protein responses in inactive lesions; neuronal/axonal specific processes in chronic active lesions. In remyelinating lesions, de novo analyses identified axonal transport responses and adaptive immune markers, which was also supported by the most heterogeneous immunoglobulin gene expression. The signature of the normal-appearing white matter (NAWM) was more similar to control WM than to lesions: only 465 DEGs differentiated NAWM from controls, and 16 were unique. The upregulated marker CD26/DPP4 was expressed by microglia in the NAWM but by mononuclear cells in active lesions, which may indicate a special subset of microglia before the lesion develops, but also emphasizes that omics related to MS lesions should be interpreted in the context of different lesions types. While chronic active lesions were the most distinct from control WM based on the highest number of unique DEGs (n = 2213), remyelinating lesions had the highest gene expression levels, and the most different molecular map from chronic active lesions. This may suggest that these two lesion types represent two ends of the spectrum of lesion evolution in PMS. The profound changes in chronic active lesions, the predominance of synaptic/neural/axonal signatures coupled with minor inflammation may indicate end-stage irreversible molecular events responsible for this less treatable phase.

    更新日期:2019-12-11
  • Regulation of microglial TMEM119 and P2RY12 immunoreactivity in multiple sclerosis white and grey matter lesions is dependent on their inflammatory environment
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-11
    Thecla A. van Wageningen; Eva Vlaar; Gijs Kooij; Cornelis A. M. Jongenelen; Jeroen J. G. Geurts; Anne-Marie van Dam

    Multiple Sclerosis (MS) is the most common cause of acquired neurological disability in young adults, pathologically characterized by leukocyte infiltration of the central nervous system, demyelination of the white and grey matter, and subsequent axonal loss. Microglia are proposed to play a role in MS lesion formation, however previous literature has not been able to distinguish infiltrated macrophages from microglia. Therefore, in this study we utilize the microglia-specific, homeostatic markers TMEM119 and P2RY12 to characterize their immunoreactivity in MS grey matter lesions in comparison to white matter lesions. Furthermore, we assessed the immunological status of the white and grey matter lesions, as well as the responsivity of human white and grey matter derived microglia to inflammatory mediators. We are the first to show that white and grey matter lesions in post-mortem human material differ in their immunoreactivity for the homeostatic microglia-specific markers TMEM119 and P2RY12. In particular, whereas immunoreactivity for TMEM119 and P2RY12 is decreased in the center of WMLs, immunoreactivity for both markers is not altered in GMLs. Based on data from post-mortem human microglia cultures, treated with IL-4 or IFNγ+LPS and on counts of CD3+ or CD20+ lymphocytes in lesions, we show that downregulation of TMEM119 and P2RY12 immunoreactivity in MS lesions corresponds with the presence of lymphocytes and lymphocyte-derived cytokines within the parenchyma but not in the meninges. Furthermore, the presence of TMEM119+ and partly P2RY12+ microglia in pre-active lesions as well as in the rim of active white and grey matter lesions, in addition to TMEM119+ and P2RY12+ rod-like microglia in subpial grey matter lesions suggest that blocking the entrance of lymphocytes into the CNS of MS patients may not interfere with all possible effects of TMEM119+ and P2RY12+ microglia in both white and grey matter MS lesions.

    更新日期:2019-12-11
  • Immune landscapes associated with different glioblastoma molecular subtypes
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-11-29
    Maria Martinez-Lage; Timothy M. Lynch; Yingtao Bi; Carolina Cocito; Gregory P. Way; Sharmistha Pal; Josephine Haller; Rachel E. Yan; Amy Ziober; Aivi Nguyen; Manoj Kandpal; Donald M. O’Rourke; Jeffrey P. Greenfield; Casey S. Greene; Ramana V. Davuluri; Nadia Dahmane

    Recent work has highlighted the tumor microenvironment as a central player in cancer. In particular, interactions between tumor and immune cells may help drive the development of brain tumors such as glioblastoma multiforme (GBM). Despite significant research into the molecular classification of glioblastoma, few studies have characterized in a comprehensive manner the immune infiltrate in situ and within different GBM subtypes. In this study, we use an unbiased, automated immunohistochemistry-based approach to determine the immune phenotype of the four GBM subtypes (classical, mesenchymal, neural and proneural) in a cohort of 98 patients. Tissue Micro Arrays (TMA) were stained for CD20 (B lymphocytes), CD5, CD3, CD4, CD8 (T lymphocytes), CD68 (microglia), and CD163 (bone marrow derived macrophages) antibodies. Using automated image analysis, the percentage of each immune population was calculated with respect to the total tumor cells. Mesenchymal GBMs displayed the highest percentage of microglia, macrophage, and lymphocyte infiltration. CD68+ and CD163+ cells were the most abundant cell populations in all four GBM subtypes, and a higher percentage of CD163+ cells was associated with a worse prognosis. We also compared our results to the relative composition of immune cell type infiltration (using RNA-seq data) across TCGA GBM tumors and validated our results obtained with immunohistochemistry with an external cohort and a different method. The results of this study offer a comprehensive analysis of the distribution and the infiltration of the immune components across the four commonly described GBM subgroups, setting the basis for a more detailed patient classification and new insights that may be used to better apply or design immunotherapies for GBM.

    更新日期:2019-12-11
  • Magnetic resonance imaging brain atrophy assessment in primary age-related tauopathy (PART)
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-09
    Miguel Quintas-Neves; Merilee A. Teylan; Lilah Besser; João Soares-Fernandes; Charles N. Mock; Walter A. Kukull; John F. Crary; Tiago Gil Oliveira

    Alzheimer disease (AD) is a neurodegenerative disorder characterized pathologically by the accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs). Recently, primary age-related tauopathy (PART) has been described as a new anatomopathological disorder where NFTs are the main feature in the absence of neuritic plaques. However, since PART has mainly been studied in post-mortem patient brains, not much is known about the clinical or neuroimaging characteristics of PART. Here, we studied the clinical brain imaging characteristics of PART focusing on neuroanatomical vulnerability by applying a previously validated multiregion visual atrophy scale. We analysed 26 cases with confirmed PART with paired clinical magnetic resonance imaging (MRI) acquisitions. In this selected cohort we found that upon correcting for the effect of age, there is increased atrophy in the medial temporal region with increasing Braak staging (r = 0.3937, p = 0.0466). Upon controlling for Braak staging effect, predominantly two regions, anterior temporal (r = 0.3638, p = 0.0677) and medial temporal (r = 0.3836, p = 0.053), show a trend for increased atrophy with increasing age. Moreover, anterior temporal lobe atrophy was associated with decreased semantic memory/language (r = − 0.5823, p = 0.0056; and r = − 0.6371, p = 0.0019, respectively), as was medial temporal lobe atrophy (r = − 0.4445, p = 0.0435). Overall, these findings support that PART is associated with medial temporal lobe atrophy and predominantly affects semantic memory/language. These findings highlight that other factors associated with aging and beyond NFTs could be involved in PART pathophysiology.

    更新日期:2019-12-11
  • Tau- but not Aß -pathology enhances NMDAR-dependent depotentiation in AD-mouse models
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-09
    Enrico Faldini; Tariq Ahmed; Luc Bueé; David Blum; Detlef Balschun

    Many mouse models of Alzheimer’s disease (AD) exhibit impairments in hippocampal long-term-potentiation (LTP), seemingly corroborating the strong correlation between synaptic loss and cognitive decline reported in human studies. In other AD mouse models LTP is unaffected, but other defects in synaptic plasticity may still be present. We recently reported that THY-Tau22 transgenic mice, that overexpress human Tau protein carrying P301S and G272 V mutations and show normal LTP upon high-frequency-stimulation (HFS), develop severe changes in NMDAR mediated long-term-depression (LTD), the physiological counterpart of LTP. In the present study, we focused on putative effects of AD-related pathologies on depotentiation (DP), another form of synaptic plasticity. Using a novel protocol to induce DP in the CA1-region, we found in 11–15 months old male THY-Tau22 and APPPS1–21 transgenic mice that DP was not deteriorated by Aß pathology while significantly compromised by Tau pathology. Our findings advocate DP as a complementary form of synaptic plasticity that may help in elucidating synaptic pathomechanisms associated with different types of dementia.

    更新日期:2019-12-09
  • Epidemiological pathology of Aβ deposition in the ageing brain in CFAS: addition of multiple Aβ-derived measures does not improve dementia assessment using logistic regression and machine learning approaches
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-05
    S. B. Wharton; D. Wang; C. Parikh; F. E. Matthews; C. Brayne; P. G. Ince

    Aβ-amyloid deposition is a key feature of Alzheimer’s disease, but Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessment, based on neuritic plaque density, shows a limited relationships to dementia. Thal phase is based on a neuroanatomical hierarchy of Aβ-deposition, and in combination with Braak neurofibrillary tangle staging also allows derivation of primary age-related tauopathy (PART). We sought to determine whether Thal Aβ phase predicts dementia better than CERAD in a population-representative cohort (n = 186) derived from the Cognitive Function and Ageing Study (CFAS). Cerebral amyloid angiopathy (CAA) was quantitied as the number of neuroanatomical areas involved and cases meeting criteria for PART were defined to determine if they are a distinct pathological group within the ageing population. Agreement with the Thal scheme was excellent. In univariate analysis Thal phase performed less well as a predictor of dementia than CERAD, Braak or CAA. Logistic regression, decision tree and linear discriminant analysis were performed for multivariable analysis, with similar results. Thal phase did not provide a better explanation of dementia than CERAD, and there was no additional benefit to including more than one assessment of Aβ in the model. Number of areas involved by CAA was highly correlated with assessment based on a severity score (p < 0.001). The presence of capillary involvement (CAA type I) was associated with higher Thal phase and Braak stage (p < 0.001). CAA was not associated with microinfarcts (p = 0.1). Cases satisfying pathological criteria for PART were present at a frequency of 10.2% but were not older and did not have a higher likelihood of dementia than a comparison group of individuals with similar Braak stage but with more Aβ. They also did not have higher hippocampal-tau stage, although PART was weakly associated with increased presence of thorn-shaped astrocytes (p = 0.048), suggesting common age-related mechanisms. Thal phase is highly applicable in a population-representative setting and allows definition of pathological subgroups, such as PART. Thal phase, plaque density, and extent and type of CAA measure different aspects of Aβ pathology, but addition of more than one Aβ measure does not improve dementia prediction, probably because these variables are highly correlated. Machine learning predictions reveal the importance of combining neuropathological measurements for the assessment of dementia.

    更新日期:2019-12-06
  • The transcriptional coactivator and histone acetyltransferase CBP regulates neural precursor cell development and migration
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-05
    Melanie Schoof; Michael Launspach; Dörthe Holdhof; Lynhda Nguyen; Verena Engel; Severin Filser; Finn Peters; Jana Immenschuh; Malte Hellwig; Judith Niesen; Volker Mall; Birgit Ertl-Wagner; Christian Hagel; Michael Spohn; Beat Lutz; Jan Sedlacik; Daniela Indenbirken; Daniel J. Merk; Ulrich Schüller

    CREB (cyclic AMP response element binding protein) binding protein (CBP, CREBBP) is a ubiquitously expressed transcription coactivator with intrinsic histone acetyltransferase (KAT) activity. Germline mutations within the CBP gene are known to cause Rubinstein-Taybi syndrome (RSTS), a developmental disorder characterized by intellectual disability, specific facial features and physical anomalies. Here, we investigate mechanisms of CBP function during brain development in order to elucidate morphological and functional mechanisms underlying the development of RSTS. Due to the embryonic lethality of conventional CBP knockout mice, we employed a tissue specific knockout mouse model (hGFAP-cre::CBPFl/Fl, mutant mouse) to achieve a homozygous deletion of CBP in neural precursor cells of the central nervous system. Our findings suggest that CBP plays a central role in brain size regulation, correct neural cell differentiation and neural precursor cell migration. We provide evidence that CBP is both important for stem cell viability within the ventricular germinal zone during embryonic development and for unhindered establishment of adult neurogenesis. Prominent histological findings in adult animals include a significantly smaller hippocampus with fewer neural stem cells. In the subventricular zone, we observe large cell aggregations at the beginning of the rostral migratory stream due to a migration deficit caused by impaired attraction from the CBP-deficient olfactory bulb. The cerebral cortex of mutant mice is characterized by a shorter dendrite length, a diminished spine number, and a relatively decreased number of mature spines as well as a reduced number of synapses. In conclusion, we provide evidence that CBP is important for neurogenesis, shaping neuronal morphology, neural connectivity and that it is involved in neuronal cell migration. These findings may help to understand the molecular basis of intellectual disability in RSTS patients and may be employed to establish treatment options to improve patients’ quality of life.

    更新日期:2019-12-06
  • Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer’s disease and regulates axonal transport and processing of the amyloid precursor protein
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-05
    Gábor M. Mórotz; Elizabeth B. Glennon; Jenny Greig; Dawn H. W. Lau; Nishita Bhembre; Francesca Mattedi; Nadine Muschalik; Wendy Noble; Alessio Vagnoni; Christopher C. J. Miller

    Damage to axonal transport is an early pathogenic event in Alzheimer’s disease. The amyloid precursor protein (APP) is a key axonal transport cargo since disruption to APP transport promotes amyloidogenic processing of APP. Moreover, altered APP processing itself disrupts axonal transport. The mechanisms that regulate axonal transport of APP are therefore directly relevant to Alzheimer’s disease pathogenesis. APP is transported anterogradely through axons on kinesin-1 motors and one route for this transport involves calsyntenin-1, a type-1 membrane spanning protein that acts as a direct ligand for kinesin-1 light chains (KLCs). Thus, loss of calsyntenin-1 disrupts APP axonal transport and promotes amyloidogenic processing of APP. Phosphorylation of KLC1 on serine-460 has been shown to reduce anterograde axonal transport of calsyntenin-1 by inhibiting the KLC1-calsyntenin-1 interaction. Here we demonstrate that in Alzheimer’s disease frontal cortex, KLC1 levels are reduced and the relative levels of KLC1 serine-460 phosphorylation are increased; these changes occur relatively early in the disease process. We also show that a KLC1 serine-460 phosphomimetic mutant inhibits axonal transport of APP in both mammalian neurons in culture and in Drosophila neurons in vivo. Finally, we demonstrate that expression of the KLC1 serine-460 phosphomimetic mutant promotes amyloidogenic processing of APP. Together, these results suggest that increased KLC1 serine-460 phosphorylation contributes to Alzheimer’s disease.

    更新日期:2019-12-06
  • Single-nucleus chromatin accessibility reveals intratumoral epigenetic heterogeneity in IDH1 mutant gliomas
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-05
    Ruslan Al-Ali; Katharina Bauer; Jong-Whi Park; Ruba Al Abdulla; Valentina Fermi; Andreas von Deimling; Christel Herold-Mende; Jan-Philipp Mallm; Carl Herrmann; Wolfgang Wick; Şevin Turcan

    The presence of genome-wide DNA hypermethylation is a hallmark of lower grade gliomas (LGG) with isocitrate dehydrogenase (IDH) mutations. Further molecular classification of IDH mutant gliomas is defined by the presence (IDHmut-codel) or absence (IDHmut-noncodel) of hemizygous codeletion of chromosome arms 1p and 19q. Despite the DNA hypermethylation seen in bulk tumors, intra-tumoral heterogeneity at the epigenetic level has not been thoroughly analyzed. To address this question, we performed the first epigenetic profiling of single cells in a cohort of 5 gliomas with IDH1 mutation using single nucleus Assay for Transposase-Accessible Chromatin with high-throughput sequencing (snATAC-seq). Using the Fluidigm HT IFC microfluidics platform, we generated chromatin accessibility maps from 336 individual nuclei, and identified variable promoter accessibility of non-coding RNAs in LGGs. Interestingly, local chromatin structures of several non-coding RNAs are significant factors that contribute to heterogeneity, and show increased promoter accessibility in IDHmut-noncodel samples. As an example for clinical significance of this result, we identify CYTOR as a poor prognosis factor in gliomas with IDH mutation. Open chromatin assay points to differential accessibility of non-coding RNAs as an important source of epigenetic heterogeneity within individual tumors and between molecular subgroups. Rare populations of nuclei that resemble either IDH mutant molecular group co-exist within IDHmut-noncodel and IDHmut-codel groups, and along with non-coding RNAs may be an important issue to consider for future studies, as they may help guide predict treatment response and relapse. A web-based explorer for the data is available at shiny.turcanlab.org.

    更新日期:2019-12-06
  • Mosaic PTEN alteration in the neural crest during embryogenesis results in multiple nervous system hamartomas
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-03
    Alice Goldenberg; Florent Marguet; Vianney Gilard; Aude-Marie Cardine; Adnan Hassani; François Doz; Sophie Radi; Stéphanie Vasseur; Jacqueline Bou; Maud Branchaud; Claude Houdayer; Stéphanie Baert-Desurmont; Annie Laquerriere; Thierry Frebourg

    The contribution of mosaic alterations to tumors of the nervous system and to non-malignant neurological diseases has been unmasked thanks to the development of Next Generation Sequencing (NGS) technologies. We report here the case of a young patient without any remarkable familial medical history who was first referred at 7 years of age, for an autism spectrum disorder (ASD) of Asperger type, not associated with macrocephaly. The patient subsequently presented at 10 years of age with multiple nodular lesions located within the trigeminal, facial and acoustic nerve ganglia and at the L3 level. Histological examination of this latter lesion revealed a glioneuronal hamartoma, exhibiting heterogeneous PTEN immunoreactivity, astrocyte and endothelial cell nuclei expressing PTEN, but not ganglion cells. NGS performed on the hamartoma allowed the detection of a PTEN pathogenic variant in 30% of the reads. The presence of this variant in the DNA extracted from blood and buccal swabs in 3.5 and 11% of the NGS reads, respectively, confirmed the mosaic state of the PTEN variant. The anatomical distribution of the lesions suggests that the mutational event affecting PTEN occurred in neural crest progenitors, thus explaining the absence of macrocephaly. This report shows that mosaic alteration of PTEN may result in multiple central and peripheral nervous system hamartomas and that the presence of such alteration should be considered in patients with multiple nervous system masses, even in the absence of cardinal features of PTEN hamartoma tumor syndrome, especially macrocephaly.

    更新日期:2019-12-04
  • A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-03
    Ebru Ercan-Herbst; Jens Ehrig; David C. Schöndorf; Annika Behrendt; Bernd Klaus; Borja Gomez Ramos; Nuria Prat Oriol; Christian Weber; Dagmar E. Ehrnhoefer

    Tau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer’s disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0–I, II or III–IV, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We found that soluble tau multimers are strongly increased at Braak stages III–IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs or misfolded oligomers at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau multimerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble multimers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs. These findings shed light on early PTM changes of tau during AD pathogenesis in human brains.

    更新日期:2019-12-04
  • Luminescent conjugated oligothiophenes distinguish between α-synuclein assemblies of Parkinson’s disease and multiple system atrophy
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-03
    Therése Klingstedt; Bernardino Ghetti; Janice L. Holton; Helen Ling; K. Peter R. Nilsson; Michel Goedert

    Synucleinopathies [Parkinson’s disease with or without dementia, dementia with Lewy bodies and multiple system atrophy] are neurodegenerative diseases that are defined by the presence of filamentous α-synuclein inclusions. We investigated the ability of luminescent conjugated oligothiophenes to stain the inclusions of Parkinson’s disease and multiple system atrophy. They stained the Lewy pathology of Parkinson’s disease and the glial cytoplasmic inclusions of multiple system atrophy. Spectral analysis of HS-68-stained inclusions showed a red shift in multiple system atrophy, but the difference with Parkinson’s disease was not significant. However, when inclusions were double-labelled for HS-68 and an antibody specific for α-synuclein phosphorylated at S129, they could be distinguished based on colour shifts with blue designated for Parkinson’s disease and red for multiple system atrophy. The inclusions of Parkinson’s disease and multiple system atrophy could also be distinguished using fluorescence lifetime imaging. These findings are consistent with the presence of distinct conformers of assembled α-synuclein in Parkinson’s disease and multiple system atrophy.

    更新日期:2019-12-04
  • The amyloid-β degradation intermediate Aβ34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer’s disease
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-03
    Tunahan Kirabali; Serena Rigotti; Alessandro Siccoli; Filip Liebsch; Adeola Shobo; Christoph Hock; Roger M. Nitsch; Gerhard Multhaup; Luka Kulic

    An impairment of amyloid β-peptide (Aβ) clearance is suggested to play a key role in the pathogenesis of sporadic Alzheimer’s disease (AD). Amyloid degradation is mediated by various mechanisms including fragmentation by enzymes like neprilysin, matrix metalloproteinases (MMPs) and a recently identified amyloidolytic activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 cleavage of Aβ40 and Aβ42 results in the formation of a common Aβ34 intermediate which was found elevated in cerebrospinal fluid levels of patients at the earliest disease stages. To further investigate the role of Aβ34 as a marker for amyloid clearance in AD, we performed a systematic and comprehensive analysis of Aβ34 immunoreactivity in hippocampal and cortical post-mortem brain tissue from AD patients and non-demented elderly individuals. In early Braak stages, Aβ34 was predominantly detectable in a subset of brain capillaries associated with pericytes, while in later disease stages, in clinically diagnosed AD, this pericyte-associated Aβ34 immunoreactivity was largely lost. Aβ34 was also detected in isolated human cortical microvessels associated with brain pericytes and its levels correlated with Aβ40, but not with Aβ42 levels. Moreover, a significantly decreased Aβ34/Aβ40 ratio was observed in microvessels from AD patients in comparison to non-demented controls suggesting a reduced proteolytic degradation of Aβ40 to Aβ34 in AD. In line with the hypothesis that pericytes at the neurovascular unit are major producers of Aβ34, biochemical studies in cultured human primary pericytes revealed a time and dose dependent increase of Aβ34 levels upon treatment with recombinant Aβ40 peptides while Aβ34 production was impaired when Aβ40 uptake was reduced or BACE1 activity was inhibited. Collectively, our findings indicate that Aβ34 is generated by a novel BACE1-mediated Aβ clearance pathway in pericytes of brain capillaries. As amyloid clearance is significantly reduced in AD, impairment of this pathway might be a major driver of the pathogenesis in sporadic AD.

    更新日期:2019-12-04
  • Secernin-1 is a novel phosphorylated tau binding protein that accumulates in Alzheimer’s disease and not in other tauopathies
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-03
    Geoffrey Pires; Sacha McElligott; Shiron Drusinsky; Glenda Halliday; Marie-Claude Potier; Thomas Wisniewski; Eleanor Drummond

    We recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer’s disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT, n = 21; Moderate NFT, n = 22; Low/No NFT, n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and AD-related neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis – Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick’s disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Co-immunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.

    更新日期:2019-12-04
  • KCC2 expression levels are reduced in post mortem brain tissue of Rett syndrome patients
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-03
    Lisa Hinz; Joan Torrella Barrufet; Vivi M. Heine

    Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MECP2) gene. Deficient K+-Cl—co-transporter 2 (KCC2) expression is suggested to play a key role in the neurodevelopmental delay in RTT patients’ neuronal networks. KCC2 is a major player in neuronal maturation by supporting the GABAergic switch, through the regulation of neuronal chlorine homeostasis. Previous studies suggest that MeCP2 mutations lead to changed KCC2 expression levels, thereby causing a disturbance in excitation/inhibition (E/I) balance. To investigate this, we performed protein and RNA expression analysis on post mortem brain tissue from RTT patients and healthy controls. We showed that KCC2 expression, in particular the KCC2a isoform, is relatively decreased in RTT patients. The expression of Na+-K+-Cl− co-transporter 1 (NKCC1), responsible for the inward transport of chlorine, is not affected, leading to a reduced KCC2/NKCC1 ratio in RTT brains. Our report confirms KCC2 expression alterations in RTT patients in human brain tissue, which is in line with other studies, suggesting affected E/I balance could underlie neurodevelopmental defects in RTT patients.

    更新日期:2019-12-04
  • A metastable subproteome underlies inclusion formation in muscle proteinopathies
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-03
    Prajwal Ciryam; Matthew Antalek; Fernando Cid; Gian Gaetano Tartaglia; Christopher M. Dobson; Anne-Katrin Guettsches; Britta Eggers; Matthias Vorgerd; Katrin Marcus; Rudolf A. Kley; Richard I. Morimoto; Michele Vendruscolo; Conrad C. Weihl

    Protein aggregation is a pathological feature of neurodegenerative disorders. We previously demonstrated that protein inclusions in the brain are composed of supersaturated proteins, which are abundant and aggregation-prone, and form a metastable subproteome. It is not yet clear, however, whether this phenomenon is also associated with non-neuronal protein conformational disorders. To respond to this question, we analyzed proteomic datasets from biopsies of patients with genetic and acquired protein aggregate myopathy (PAM) by quantifying the changes in composition, concentration and aggregation propensity of proteins in the fibers containing inclusions and those surrounding them. We found that a metastable subproteome is present in skeletal muscle from healthy patients. The expression of this subproteome escalate as proteomic samples are taken more proximal to the pathologic inclusion, eventually exceeding its solubility limits and aggregating. While most supersaturated proteins decrease or maintain steady abundance across healthy fibers and inclusion-containing fibers, proteins within the metastable subproteome rise in abundance, suggesting that they escape regulation. Taken together, our results show in the context of a human conformational disorder that the supersaturation of a metastable subproteome underlies widespread aggregation and correlates with the histopathological state of the tissue.

    更新日期:2019-12-04
  • Circadian sleep/wake-associated cells show dipeptide repeat protein aggregates in C9orf72-related ALS and FTLD cases
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-12-02
    Lieselot Dedeene; Evelien Van Schoor; Rik Vandenberghe; Philip Van Damme; Koen Poesen; Dietmar Rudolf Thal

    Motor-, behavior- and/or cognition-related symptoms are key hallmarks in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 pathology (FTLD-TDP), respectively. It has been reported that these patients also experience sleep disturbances, which might implicate a disturbed circadian rhythm of the sleep/wake cycle. It remains unknown, however, whether cells involved in the circadian sleep/wake cycle are affected by ALS- and FTLD-related neuropathological changes including phosphorylated TDP-43 (pTDP-43) aggregates and dipeptide repeat protein (DPR) inclusions resulting from the C9orf72 hexanucleotide repeat expansion. Immunohistochemistry for DPR and pTDP-43 pathology was performed in post-mortem hypothalamus and pineal gland tissue of patients with ALS and/or FTLD-TDP with and without the C9orf72 repeat expansion and healthy controls. Circadian sleep/wake-associated cells, including pinealocytes and hypothalamic neurons related to the suprachiasmatic nucleus (SCN), were microscopically assessed. We observed numerous DPR inclusions (poly(GA), poly(GP), poly(GR) and poly(PR)) in the pinealocytes and few poly(GA) inclusions in the SCN-related neurons in C9orf72-related ALS and/or FTLD-TDP cases. These circadian sleep/wake-associated cells, however, were devoid of pTDP-43 pathology both in C9orf72- and nonC9orf72-related ALS and/or FTLD-TDP cases. Our neuropathological findings show that pinealocytes and, to a lesser extent, SCN-related neurons are affected by DPR pathology. This may reflect an involvement of these cells in sleep/wake disturbances observed in ALS and/or FTLD-TDP patients.

    更新日期:2019-12-02
  • Intraventricular meningiomas frequently harbor NF2 mutations but lack common genetic alterations in TRAF7, AKT1, SMO, KLF4, PIK3CA, and TERT
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-08-30
    Gerhard Jungwirth; Rolf Warta; Christopher Beynon; Felix Sahm; Andreas von Deimling; Andreas Unterberg; Christel Herold-Mende; Christine Jungk

    Intraventricular meningiomas (IVMs) account for less than 5% of all intracranial meningiomas; hence their molecular phenotype remains unknown. In this study, we were interested whether genetic alterations in IVMs differ from meningiomas in other locations and analyzed our institutional series with respect to clinical and molecular characteristics. A total of 25 patients with surgical removal of an IVM at our department between 1986 and 2018 were identified from our institutional database. Median progression-free survival (PFS) was 79 months (range of 2–319 months) and PFS at 5 years was 86%. Corresponding tumor tissue was available for 18 patients including one matching recurrence and was subjected to targeted panel sequencing of 130 selected genes frequently mutated in brain cancers by applying a custom hybrid capture approach on a NextSeq500 instrument. Loss of chromosome 22q and 1p occurred frequently in 89 and 44% of cases. Deleterious NF2 mutations were found in 44% of IVMs (n = 8/18). In non-NF2-mutated IVMs, previously reported genetic alterations including TRAF7, AKT1, SMO, KLF4, PIK3CA, and TERT were lacking, suggesting alternative genes in the pathogenesis of non-NF2 IVMs. In silico analysis revealed possible damaging mutations of APC, GABRA6, GSE1, KDR, and two SMO missense mutations differing from previously reported ones. Interestingly, all WHO°II IVMs (n = 3) harbored SMARCB1 and SMARCA4 mutations, indicating a role of the SWI/SNF chromatin remodeling complex in aggressive IVMs.

    更新日期:2019-11-28
  • Aβ43 in human Alzheimer’s disease: effects of active Aβ42 immunization
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-02
    Lieke Jäkel; Delphine Boche; James A. R. Nicoll; Marcel M. Verbeek

    Neuropathological follow-up of patients with Alzheimer’s disease (AD) who participated in the first clinical trial of Amyloid-β 42 (Aβ42) immunization (AN1792, Elan Pharmaceuticals) has shown that immunization can induce removal of Aβ42 and Aβ40 from plaques, whereas analysis of the cerebral vessels has shown increased levels of these Aβ peptides in cerebral amyloid angiopathy (CAA). Aβ43 has been less frequently studied in AD, but its aggregation propensity and neurotoxic properties suggest it may have an important pathogenic role. In the current study we show by using immunohistochemistry that in unimmunized AD patients Aβ43 is a frequent constituent of plaques (6.0% immunostained area), similar to Aβ42 (3.9% immunostained area). Aβ43 immunostained area was significantly higher than that of Aβ40 (2.3%, p = 0.006). In addition, we show that Aβ43 is only a minor component of CAA in both parenchymal vessels (1.5 Aβ43-positive vessels per cm2 cortex vs. 5.3 Aβ42-positive vessels, p = 0.03, and 6.2 Aβ40-positive vessels, p = 0.045) and leptomeningeal vessels (5.6% Aβ43-positive vessels vs. 17.3% Aβ42-positive vessels, p = 0.007, and 27.4% Aβ40-positive vessels, p = 0.003). Furthermore, we have shown that Aβ43 is cleared from plaques after Aβ immunotherapy, similar to Aβ42 and Aβ40. Cerebrovascular Aβ43 levels did not change after immunotherapy.

    更新日期:2019-11-28
  • Unique α-synuclein pathology within the amygdala in Lewy body dementia: implications for disease initiation and progression
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-02
    Zachary A. Sorrentino; Marshall S. Goodwin; Cara J. Riffe; Jess-Karan S. Dhillon; Yuxing Xia; Kimberly-Marie Gorion; Niran Vijayaraghavan; Karen N. McFarland; Lawrence I. Golbe; Anthony T. Yachnis; Benoit I. Giasson

    The protein α-synuclein (αsyn) forms pathologic aggregates in a number of neurodegenerative diseases including Lewy body dementia (LBD) and Parkinson’s disease (PD). It is unclear why diseases such as LBD may develop widespread αsyn pathology, while in Alzheimer’s disease with amygdala restricted Lewy bodies (AD/ALB) the αsyn aggregates remain localized. The amygdala contains αsyn aggregates in both LBD and in AD/ALB; to understand why αsyn pathology continues to progress in LBD but not in AD/ALB, tissue from the amygdala and other regions were obtained from 14 cases of LBD, 9 cases of AD/ALB, and 4 controls for immunohistochemical and biochemical characterization. Utilizing a panel of previously characterized αsyn antibodies, numerous unique pathologies differentiating LBD and AD/ALB were revealed; particularly the presence of dense neuropil αsyn aggregates, astrocytic αsyn, and αsyn-containing dystrophic neurites within senile plaques. Within LBD, these unique pathologies were predominantly present within the amygdala. Biochemically, the amygdala in LBD prominently contained specific carboxy-truncated forms of αsyn which are highly prone to aggregate, suggesting that the amygdala may be prone to initiate development of αsyn pathology. Similar to carboxy-truncated αsyn, it was demonstrated herein that the presence of aggregation prone A53T αsyn is sufficient to drive misfolding of wild-type αsyn in human disease. Overall, this study identifies within the amygdala in LBD the presence of unique strain-like variation in αsyn pathology that may be a determinant of disease progression.

    更新日期:2019-11-28
  • Composition of the Intranuclear Inclusions of Fragile X-associated Tremor/Ataxia Syndrome
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-03
    Lisa Ma; Anthony W. Herren; Glenda Espinal; Jamie Randol; Bridget McLaughlin; Veronica Martinez-Cerdeño; Isaac N. Pessah; Randi J. Hagerman; Paul J. Hagerman

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation repeat expansion (55–200 CGG repeats) in the 5′ noncoding region of the FMR1 gene. Solitary intranuclear inclusions within FXTAS neurons and astrocytes constitute a hallmark of the disorder, yet our understanding of how and why these bodies form is limited. Here, we have discovered that FXTAS inclusions emit a distinct autofluorescence spectrum, which forms the basis of a novel, unbiased method for isolating FXTAS inclusions by preparative fluorescence-activated cell sorting (FACS). Using a combination of autofluorescence-based FACS and liquid chromatography/tandem mass spectrometry (LC-MS/MS)-based proteomics, we have identified more than two hundred proteins that are enriched within the inclusions relative to FXTAS whole nuclei. Whereas no single protein species dominates inclusion composition, highly enriched levels of conjugated small ubiquitin-related modifier 2 (SUMO 2) protein and p62/sequestosome-1 (p62/SQSTM1) protein were found within the inclusions. Many additional proteins involved with RNA binding, protein turnover, and DNA damage repair were enriched within inclusions relative to total nuclear protein. The current analysis has also allowed the first direct detection, through peptide sequencing, of endogenous FMRpolyG peptide, the product of repeat-associated non-ATG (RAN) translation of the FMR1 mRNA. However, this peptide was found only at extremely low levels and not within whole FXTAS nuclear preparations, raising the question whether endogenous RAN products exist at quantities sufficient to contribute to FXTAS pathogenesis. The abundance of the inclusion-associated ubiquitin- and SUMO-based modifiers supports a model for inclusion formation as the result of increased protein loads and elevated oxidative stress leading to maladaptive autophagy. These results highlight the need to further investigate FXTAS pathogenesis in the context of endogenous systems.

    更新日期:2019-11-28
  • Optimization of ultrastructural preservation of human brain for transmission electron microscopy after long post-mortem intervals
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-03
    Mariella Sele; Stefan Wernitznig; Saška Lipovšek; Snježana Radulović; Johannes Haybaeck; Anna Maria Birkl-Toeglhofer; Christina Wodlej; Florian Kleinegger; Stephan Sygulla; Marlene Leoni; Stefan Ropele; Gerd Leitinger

    Electron microscopy (EM) provides the necessary resolution to visualize the finer structures of nervous tissue morphology, which is important to understand healthy and pathological conditions in the brain. However, for the interpretation of the micrographs the tissue preservation is crucial. The quality of the tissue structure is mostly influenced by the post mortem interval (PMI), the time of death until the preservation of the tissue. Therefore, the aim of this study was to optimize the preparation-procedure for the human frontal lobe to preserve the ultrastructure as well as possible despite the long PMIs. Combining chemical pre- and post-fixation with cryo-fixation and cryo-substitution (“hybrid freezing”), it was possible to improve the preservation of the neuronal profiles of human brain samples compared to the “standard” epoxy resin embedding method. In conclusion short PMIs are generally desirable but up to a PMI of 16 h the ultrastructure can be preserved on an acceptable level with a high contrast using the “hybrid freezing” protocol described here.

    更新日期:2019-11-28
  • Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-03
    Fiona Tea; Joseph A. Lopez; Sudarshini Ramanathan; Vera Merheb; Fiona X. Z. Lee; Alicia Zou; Deepti Pilli; Ellis Patrick; Anneke van der Walt; Mastura Monif; Esther M. Tantsis; Eppie M. Yiu; Steve Vucic; Andrew P. D. Henderson; Anthony Fok; Clare L. Fraser; Jeanette Lechner-Scott; Stephen W. Reddel; Simon Broadley; Michael H. Barnett; David A. Brown; Jan D. Lunemann; Russell C. Dale; Fabienne Brilot

    Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.

    更新日期:2019-11-28
  • Encephalopathy induced by Alzheimer brain inoculation in a non-human primate
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-04
    Charlotte Gary; Suzanne Lam; Anne-Sophie Hérard; James E. Koch; Fanny Petit; Pauline Gipchtein; Stephen J. Sawiak; Raphaëlle Caillierez; Sabiha Eddarkaoui; Morvane Colin; Fabienne Aujard; Jean-Philippe Deslys; Emmanuel Brouillet; Luc Buée; Emmanuel E. Comoy; Fabien Pifferi; Jean-Luc Picq; Marc Dhenain

    Alzheimer’s disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated β-amyloid peptides (Aβ) and tau proteins. Iatrogenic induction of Aβ is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aβ. Induction of Aβ and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer’s disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aβ or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aβ depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer’s disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes.

    更新日期:2019-11-28
  • Perfusion fixation in brain banking: a systematic review
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-05
    Whitney C. McFadden; Hadley Walsh; Felix Richter; Céline Soudant; Clare H. Bryce; Patrick R. Hof; Mary Fowkes; John F. Crary; Andrew T. McKenzie

    Perfusing fixatives through the cerebrovascular system is the gold standard approach in animals to prepare brain tissue for spatial biomolecular profiling, circuit tracing, and ultrastructural studies such as connectomics. Translating these discoveries to humans requires examination of postmortem autopsy brain tissue. Yet banked brain tissue is routinely prepared using immersion fixation, which is a significant barrier to optimal preservation of tissue architecture. The challenges involved in adopting perfusion fixation in brain banks and the extent to which it improves histology quality are not well defined. We searched four databases to identify studies that have performed perfusion fixation in human brain tissue and screened the references of the eligible studies to identify further studies. From the included studies, we extracted data about the methods that they used, as well as any data comparing perfusion fixation to immersion fixation. The protocol was preregistered at the Open Science Framework: https://osf.io/cv3ys/ . We screened 4489 abstracts, 214 full-text publications, and identified 35 studies that met our inclusion criteria, which collectively reported on the perfusion fixation of 558 human brains. We identified a wide variety of approaches to perfusion fixation, including perfusion fixation of the brain in situ and ex situ, perfusion fixation through different sets of blood vessels, and perfusion fixation with different washout solutions, fixatives, perfusion pressures, and postfixation tissue processing methods. Through a qualitative synthesis of data comparing the outcomes of perfusion and immersion fixation, we found moderate confidence evidence showing that perfusion fixation results in equal or greater subjective histology quality compared to immersion fixation of relatively large volumes of brain tissue, in an equal or shorter amount of time. This manuscript serves as a resource for investigators interested in building upon the methods and results of previous research in designing their own perfusion fixation studies in human brains or other large animal brains. We also suggest several future research directions, such as comparing the in situ and ex situ approaches to perfusion fixation, studying the efficacy of different washout solutions, and elucidating the types of brain donors in which perfusion fixation is likely to result in higher fixation quality than immersion fixation.

    更新日期:2019-11-28
  • The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-12
    Viviana Pérez; Francisca Bermedo-Garcia; Diego Zelada; Felipe A. Court; Miguel Ángel Pérez; Marco Fuenzalida; Johanna Ábrigo; Claudio Cabello-Verrugio; Guillermo Moya-Alvarado; Juan Carlos Tapia; Vicente Valenzuela; Claudio Hetz; Francisca C. Bronfman; Juan Pablo Henríquez

    The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.

    更新日期:2019-11-28
  • Silver staining (Campbell-Switzer) of neuronal α-synuclein assemblies induced by multiple system atrophy and Parkinson’s disease brain extracts in transgenic mice
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-16
    Isabelle Lavenir; Daniela Passarella; Masami Masuda-Suzukake; Annabelle Curry; Janice L. Holton; Bernardino Ghetti; Michel Goedert

    Synucleinopathies [Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)] share filamentous α-synuclein assemblies in nerve cells and glial cells. We compared the abilities of brain extracts from MSA and PD patients to induce neuronal α-synuclein assembly and neurodegeneration following intracerebral injection in heterozygous mice transgenic for human mutant A53T α-synuclein. MSA extracts were more potent than PD extracts in inducing α-synuclein assembly and in causing neurodegeneration. MSA assemblies were Campbell-Switzer- and Gallyas-silver-positive, whereas PD assemblies were only Campbell-Switzer-positive, in confirmation of previous findings. However, induced α-synuclein inclusions were invariably Campbell-Switzer-positive and Gallyas-negative, irrespective of whether MSA or PD brain extracts were injected. The α-synuclein inclusions of non-injected homozygous mice transgenic for A53T α-synuclein were also Campbell-Switzer-positive and Gallyas-negative. These findings demonstrate that transgene expression and its intracellular environment dominated over the silver staining properties of the conformers of assembled α-synuclein.

    更新日期:2019-11-28
  • Epigenetic downregulation of STAT6 increases HIF-1α expression via mTOR/S6K/S6, leading to enhanced hypoxic viability of glioma cells
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-09-17
    Soo Jung Park; Hyunmi Kim; Se Hyuk Kim; Eun-hye Joe; Ilo Jou

    Multifunctional signal transducer and activator of transcription (STAT) proteins play important roles in cancer. Here, we have shown that STAT6 is epigenetically silenced in some cases of malignant glioblastoma, which facilitates cancer cell survival in a hypoxic microenvironment. This downregulation results from hypermethylation of CpG islands within the STAT6 promoter by DNA methyltransferases. STAT6 interacts with Rheb under hypoxia and inhibits mTOR/S6K/S6 signaling, in turn, inducing increased HIF-1α translation. STAT6 silencing and consequent tumor-promoting effects are additionally observed in glioma stem-like cells (GSC). Despite recent advances in cancer treatment, survival rates have shown little improvement. This is particularly true in the case of glioma, where multimodal treatment and precision medicine is needed. Our study supports the application of epigenetic restoration of STAT6 with the aid of DNA methyltransferase inhibitors, such as 5-aza-2-deoxycytidine, for treatment of STAT6-silenced gliomas.

    更新日期:2019-11-28
  • Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-08
    Dennis W. Dickson; Matthew C. Baker; Jazmyne L. Jackson; Mariely DeJesus-Hernandez; NiCole A. Finch; Shulan Tian; Michael G. Heckman; Cyril Pottier; Tania F. Gendron; Melissa E. Murray; Yingxue Ren; Joseph S. Reddy; Neill R. Graff-Radford; Bradley F. Boeve; Ronald C. Petersen; David S. Knopman; Keith A. Josephs; Leonard Petrucelli; Björn Oskarsson; John W. Sheppard; Yan W. Asmann; Rosa Rademakers; Marka van Blitterswijk

    The majority of the clinico-pathological variability observed in patients harboring a repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) remains unexplained. This expansion, which represents the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND), results in a loss of C9orf72 expression and the generation of RNA foci and dipeptide repeat (DPR) proteins. The C9orf72 protein itself plays a role in vesicular transport, serving as a guanine nucleotide exchange factor that regulates GTPases. To further elucidate the mechanisms underlying C9orf72-related diseases and to identify potential disease modifiers, we performed an extensive RNA sequencing study. We included individuals for whom frontal cortex tissue was available: FTLD and FTLD/MND patients with (n = 34) or without (n = 44) an expanded C9orf72 repeat as well as control subjects (n = 24). In total, 6706 genes were differentially expressed between these groups (false discovery rate [FDR] < 0.05). The top gene was C9orf72 (FDR = 1.41E-14), which was roughly two-fold lower in C9orf72 expansion carriers than in (disease) controls. Co-expression analysis revealed groups of correlated genes (modules) that were enriched for processes such as protein folding, RNA splicing, synaptic signaling, metabolism, and Golgi vesicle transport. Within our cohort of C9orf72 expansion carriers, machine learning uncovered interesting candidates associated with clinico-pathological features, including age at onset (vascular endothelial growth factor A [VEGFA]), C9orf72 expansion size (cyclin dependent kinase like 1 [CDKL1]), DPR protein levels (eukaryotic elongation factor 2 kinase [EEF2K]), and survival after onset (small G protein signaling modulator 3 [SGSM3]). Given the fact that we detected a module involved in vesicular transport in addition to a GTPase activator (SGSM3) as a potential modifier, our findings seem to suggest that the presence of a C9orf72 repeat expansion might hamper vesicular transport and that genes affecting this process may modify the phenotype of C9orf72-linked diseases.

    更新日期:2019-11-28
  • Profiling the unique protective properties of intracranial arterial endothelial cells
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-14
    Dorien M. A. Hermkens; Olga C. G. Stam; Nienke M. de Wit; Ruud D. Fontijn; Aldo Jongejan; Perry D. Moerland; Claire Mackaaij; Ingeborg S. E. Waas; Mat J. A. P. Daemen; Helga E. de Vries

    Cardiovascular disorders, like atherosclerosis and hypertension, are increasingly known to be associated with vascular cognitive impairment (VCI). In particular, intracranial atherosclerosis is one of the main causes of VCI, although plaque development occurs later in time and is structurally different compared to atherosclerosis in extracranial arteries. Recent data suggest that endothelial cells (ECs) that line the intracranial arteries may exert anti-atherosclerotic effects due to yet unidentified pathways. To gain insights into underlying mechanisms, we isolated post-mortem endothelial cells from both the intracranial basilar artery (BA) and the extracranial common carotid artery (CCA) from the same individual (total of 15 individuals) with laser capture microdissection. RNA sequencing revealed a distinct molecular signature of the two endothelial cell populations of which the most prominent ones were validated by means of qPCR. Our data reveal for the first time that intracranial artery ECs exert an immune quiescent phenotype. Secondly, genes known to be involved in the response of ECs to damage (inflammation, differentiation, adhesion, proliferation, permeability and oxidative stress) are differentially expressed in intracranial ECs compared to extracranial ECs. Finally, Desmoplakin (DSP) and Hop Homeobox (HOPX), two genes expressed at a higher level in intracranial ECs, and Sodium Voltage-Gated Channel Beta Subunit 3 (SCN3B), a gene expressed at a lower level in intracranial ECs compared to extracranial ECs, were shown to be responsive to shear stress and/or hypoxia. With our data we present a set of intracranial-specific endothelial genes that may contribute to its protective phenotype, thereby supporting proper perfusion and consequently may preserve cognitive function. Deciphering the molecular regulation of the vascular bed in the brain may lead to the identification of novel potential intervention strategies to halt vascular associated disorders, such as atherosclerosis and vascular cognitive dysfunction.

    更新日期:2019-11-28
  • Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-14
    Hélène Party; Cléo Dujarrier; Marie Hébert; Sophie Lenoir; Sara Martinez de Lizarrondo; Raphaël Delépée; Claudine Fauchon; Marie-Christine Bouton; Pauline Obiang; Olivier Godefroy; Etienne Save; Laurent Lecardeur; Joëlle Chabry; Denis Vivien; Véronique Agin

    Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, thus ranking among the major causes of disability and morbidity worldwide. To date, genetic and environmental determinants of MDD remain mostly unknown. Here, we investigated whether and how the Plasminogen Activator Inhibitor-1 (PAI-1) may contribute to MDD. We first examined the phenotype of PAI-1 knockout (PAI-1−/−) and wild-type (PAI-1+/+) male mice with a range of behavioral tests assessing depressive-like behaviors (n = 276). We next investigated the mechanisms relating PAI-1 to MDD using molecular, biochemical and pharmacological analyzes. We demonstrate here that PAI-1 plays a key role in depression by a mechanism independent of the tissue-type Plasminogen Activator (tPA) – Brain-Derived Neurotrophic Factor (BDNF) axis, but associated with impaired metabolisms of serotonin and dopamine. Our data also reveal that PAI-1 interferes with therapeutic responses to selective serotonin reuptake inhibitors (escitalopram, fluoxetine). We thus highlight a new genetic preclinical model of depression, with the lack of PAI-1 as a factor of predisposition to MDD. Altogether, these original data reveal that PAI-1 should be now considered as a key player of MDD and as a potential target for the development of new drugs to cure depressive patients resistant to current treatments.

    更新日期:2019-11-28
  • Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-15
    Wiebke A. Rehorst; Maximilian P. Thelen; Hendrik Nolte; Clara Türk; Sebahattin Cirak; Jonathan M. Peterson; G. William Wong; Brunhilde Wirth; Marcus Krüger; Dominic Winter; Min Jeong Kye

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.

    更新日期:2019-11-28
  • Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-16
    Mirca S. Saurty-Seerunghen; Léa Bellenger; Elias A. El-Habr; Virgile Delaunay; Delphine Garnier; Hervé Chneiweiss; Christophe Antoniewski; Ghislaine Morvan-Dubois; Marie-Pierre Junier

    Glioblastoma cell ability to adapt their functioning to microenvironment changes is a source of the extensive intra-tumor heterogeneity characteristic of this devastating malignant brain tumor. A systemic view of the metabolic pathways underlying glioblastoma cell functioning states is lacking. We analyzed public single cell RNA-sequencing data from glioblastoma surgical resections, which offer the closest available view of tumor cell heterogeneity as encountered at the time of patients’ diagnosis. Unsupervised analyses revealed that information dispersed throughout the cell transcript repertoires encoded the identity of each tumor and masked information related to cell functioning states. Data reduction based on an experimentally-defined signature of transcription factors overcame this hurdle. It allowed cell grouping according to their tumorigenic potential, regardless of their tumor of origin. The approach relevance was validated using independent datasets of glioblastoma cell and tissue transcriptomes, patient-derived cell lines and orthotopic xenografts. Overexpression of genes coding for amino acid and lipid metabolism enzymes involved in anti-oxidative, energetic and cell membrane processes characterized cells with high tumorigenic potential. Modeling of their expression network highlighted the very long chain polyunsaturated fatty acid synthesis pathway at the core of the network. Expression of its most downstream enzymatic component, ELOVL2, was associated with worsened patient survival, and required for cell tumorigenic properties in vivo. Our results demonstrate the power of signature-driven analyses of single cell transcriptomes to obtain an integrated view of metabolic pathways at play within the heterogeneous cell landscape of patient tumors.

    更新日期:2019-11-28
  • The prognostic role of IDH mutations in homogeneously treated patients with anaplastic astrocytomas and glioblastomas
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-17
    Arne Christians; Antonia Adel-Horowski; Rouzbeh Banan; Ulrich Lehmann; Stephan Bartels; Felix Behling; Alonso Barrantes-Freer; Christine Stadelmann; Veit Rohde; Florian Stockhammer; Christian Hartmann

    The detection of IDH mutations in patients with diffusely infiltrating malignant astrocytomas resulted in substantial modifications in the concept of WHO classification of these tumors. An important underlying observation was that patients with anaplastic astrocytomas (AA) without IDH mutation had a clinical course similar to that of patients with glioblastomas (GBM). The underlying observations of the German Glioma Network and NOA-04, however, were based on mixed patient cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually had radiotherapy or chemotherapy only. This intrinsic shortcoming of the study raised the question of whether patients with AA, IDH wildtype, WHO grade III, might have better prognosis if treated with combined radiochemotherapy than patients with GBM receiving the same combination therapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of an IDH mutation are still important if neither vascular proliferation nor necrosis are detectable. All patients in the cohort investigated here with the diagnosis of AA or GBM were subjected to a combined radiochemotherapy according to the Stupp protocol independently of the histopathological diagnosis. Thus, the analysis of these patients allows to clarify whether patients with AA, IDH wildtype, WHO grade III have a prognosis similar to that of GBM, IDH wildtype, WHO grade IV, even under equivalent therapeutic conditions. We determined the IDH1 and IDH2 status by sequencing, the MGMT status by pyrosequencing after bisulfite treatment and the EGFR status of the patients by FISH. In fact, the patients with the histopathological diagnosis of an AA IDH wild-type under similar aggressive therapy showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a GBM (mOS 13 months). Instead, patients with an AA and an IDH mutation receiving the same therapy had a mOS of 54 months. Thus, it can be concluded that in the absence of an IDH mutation, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ actually lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and an IDH mutation are examined, there is still a difference between patients with necrosis and/or vascular proliferation and those whose tumors do not show such characteristics. Accordingly, in patients with malignant astrocytomas with IDH mutation it can be concluded that a histological differentiation between AA IDH mutated and GBM IDH mutated remains beneficial from a prognostic perspective.

    更新日期:2019-11-28
  • Correction to: Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-18
    Praveena Manogaran; Marijana Samardzija; Anaïs Nura Schad; Carla Andrea Wicki; Christine Walker-Egger; Markus Rudin; Christian Grimm; Sven Schippling

    In the original publication of this article [1], Fig. 10 contained two panels “C” as panel “F” was accidentally omitted. The incorrect (Fig. 1) and correct (Fig. 2) versions are published in this correction article.

    更新日期:2019-11-28
  • Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-22
    Li-Chun Lin; Alissa L. Nana; Mackenzie Hepker; Ji-Hye Lee Hwang; Stephanie E. Gaus; Salvatore Spina; Celica G. Cosme; Li Gan; Lea T. Grinberg; Daniel H. Geschwind; Giovanni Coppola; Howard J. Rosen; Bruce L. Miller; William W. Seeley

    Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick’s disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied.

    更新日期:2019-11-28
  • Chronic nigral neuromodulation aggravates behavioral deficits and synaptic changes in an α-synuclein based rat model for Parkinson’s disease
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-22
    Teresa Torre-Muruzabal; Jens Devoght; Chris Van den Haute; Bert Brône; Anke Van der Perren; Veerle Baekelandt

    Aggregation of alpha-synuclein (α-SYN) is the pathological hallmark of several diseases named synucleinopathies, including Parkinson’s disease (PD), which is the most common neurodegenerative motor disorder. Alpha-SYN has been linked to synaptic function both in physiological and pathological conditions. However, the exact link between neuronal activity, α-SYN toxicity and disease progression in PD is not clear. In this study, we aimed to investigate the effect of chronic neuromodulation in an α-SYN-based rat model for PD using chemogenetics. To do this, we expressed excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) combined with mutant A53T α-SYN, using two different recombinant adeno-associated viral (rAAV) vectors (serotypes 2/7 and 2/8) in rat substantia nigra (SN) and investigated the effect on motor behavior, synapses and neuropathology. We found that chronic neuromodulation aggravates motor deficits induced by α-SYN, without altering dopaminergic neurodegeneration. In addition, neuronal activation led to changes in post-translational modification and subcellular localization of α-SYN, linking neuronal activity to the pathophysiological role of α-SYN in PD.

    更新日期:2019-11-28
  • Synaptic localization of C9orf72 regulates post-synaptic glutamate receptor 1 levels
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-24
    Shangxi Xiao; Paul M. McKeever; Agnes Lau; Janice Robertson

    A hexanucleotide repeat expansion in a noncoding region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Reduction of select or total C9orf72 transcript and protein levels is observed in postmortem C9-ALS/FTD tissue, and loss of C9orf72 orthologues in zebrafish and C. elegans results in motor deficits. However, how the reduction in C9orf72 in ALS and FTD might contribute to the disease process remains poorly understood. It has been shown that C9orf72 interacts and forms a complex with SMCR8 and WDR41, acting as a guanine exchange factor for Rab GTPases. Given the known synaptosomal compartmentalization of C9orf72-interacting Rab GTPases, we hypothesized that C9orf72 localization to synaptosomes would be required for the regulation of Rab GTPases and receptor trafficking. This study combined synaptosomal and post-synaptic density preparations together with a knockout-confirmed monoclonal antibody for C9orf72 to assess the localization and role of C9orf72 in the synaptosomes of mouse forebrains. Here, we found C9orf72 to be localized to both the pre- and post-synaptic compartment, as confirmed by both post-synaptic immunoprecipitation and immunofluorescence labelling. In C9orf72 knockout (C9-KO) mice, we demonstrated that pre-synaptic Rab3a, Rab5, and Rab11 protein levels remained stable compared with wild-type littermates (C9-WT). Strikingly, post-synaptic preparations from C9-KO mouse forebrains demonstrated a complete loss of Smcr8 protein levels, together with a significant downregulation of Rab39b and a concomitant upregulation of GluR1 compared with C9-WT mice. We confirmed the localization of Rab39b downregulation and GluR1 upregulation to the dorsal hippocampus of C9-KO mice by immunofluorescence. These results indicate that C9orf72 is essential for the regulation of post-synaptic receptor levels, and implicates loss of C9orf72 in contributing to synaptic dysfunction and related excitotoxicity in ALS and FTD.

    更新日期:2019-11-28
  • Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo
    Acta Neuropathol. Commun. (IF 5.883) Pub Date : 2019-10-26
    Lena Will; Sybren Portegies; Jasper van Schelt; Merel van Luyk; Dick Jaarsma; Casper C. Hoogenraad

    For the proper organization of the six-layered mammalian neocortex it is required that neurons migrate radially from their place of birth towards their designated destination. The molecular machinery underlying this neuronal migration is still poorly understood. The dynein-adaptor protein BICD2 is associated with a spectrum of human neurological diseases, including malformations of cortical development. Previous studies have shown that knockdown of BICD2 interferes with interkinetic nuclear migration in radial glial progenitor cells, and that Bicd2-deficient mice display an altered laminar organization of the cerebellum and the neocortex. However, the precise in vivo role of BICD2 in neocortical development remains unclear. By comparing cell-type specific conditional Bicd2 knock-out mice, we found that radial migration in the cortex predominantly depends on BICD2 function in post-mitotic neurons. Neuron-specific Bicd2 cKO mice showed severely impaired radial migration of late-born upper-layer neurons. BICD2 depletion in cortical neurons interfered with proper Golgi organization, and neuronal maturation and survival of cortical plate neurons. Single-neuron labeling revealed a specific role of BICD2 in bipolar locomotion. Rescue experiments with wildtype and disease-related mutant BICD2 constructs revealed that a point-mutation in the RAB6/RANBP2-binding-domain, associated with cortical malformation in patients, fails to restore proper cortical neuron migration. Together, these findings demonstrate a novel, cell-intrinsic role of BICD2 in cortical neuron migration in vivo and provide new insights into BICD2-dependent dynein-mediated functions during cortical development.

    更新日期:2019-11-28
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