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MLKL deficiency alleviates neuroinflammation and motor deficits in the α-synuclein transgenic mouse model of Parkinson’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-01 Lu Geng, Wenqing Gao, Hexige Saiyin, Yuanyuan Li, Yu Zeng, Zhifei Zhang, Xue Li, Zuolong Liu, Qiang Gao, Ping An, Ning Jiang, Xiaofei Yu, Xiangjun Chen, Suhua Li, Lei Chen, Boxun Lu, Aiqun Li, Guoyuan Chen, Yidong Shen, Haibing Zhang, Mei Tian, Zhuohua Zhang, Jixi Li
Parkinson’s disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases,
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Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer’s disease model Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-01 Qiuchen Zhao, Megi Maci, Morgan R. Miller, Heng Zhou, Fang Zhang, Moustafa Algamal, Yee Fun Lee, Steven S. Hou, Stephen J. Perle, Hoang Le, Alyssa N. Russ, Eng H. Lo, Dmitry Gerashchenko, Stephen N. Gomperts, Brian J. Bacskai, Ksenia V. Kastanenka
Alzheimer’s disease (AD) patients exhibit memory disruptions and profound sleep disturbances, including disruption of deep non-rapid eye movement (NREM) sleep. Slow-wave activity (SWA) is a major restorative feature of NREM sleep and is important for memory consolidation. We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre
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Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-29 Gizem Terzioglu, Tracy L. Young-Pearse
Recent genetic studies on Alzheimer’s disease (AD) have brought microglia under the spotlight, as loci associated with AD risk are enriched in genes expressed in microglia. Several of these genes have been recognized for their central roles in microglial functions. Increasing evidence suggests that SHIP1, the protein encoded by the AD-associated gene INPP5D, is an important regulator of microglial
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Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-28 Karen Y. He, Ekaterina A. Khramtsova, Alfredo Cabrera-Socorro, Yanfei Zhang, Shuwei Li, Brice A. J. Sarver, Bart Smets, Qingqin S. Li, Louis De Muynck, Antonio R. Parrado, Simon Lovestone, Mary Helen Black
To the editor The APOE gene is a known genetic risk factor for neurodegeneration and cardiovascular disease (CVD) [1, 2]. Beyond the known effects of APOE ε2 and APOE ε4, several rare and protective APOE variants (R154S Christchurch (APOECh), V236E Jacksonville, and R251G) have been identified recently [3, 4]. The ultra-rare APOECh mutation (NM_000041.4(APOE):c.460C > A (p.Arg154Ser)), also known as
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Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-27 Morgan Bérard, Laura Martínez-Drudis, Razan Sheta, Omar M. A. El-Agnaf, Abid Oueslati
Alpha-synuclein (α-syn) aggregation into proteinaceous intraneuronal inclusions, called Lewy bodies (LBs), is the neuropathological hallmark of Parkinson’s disease (PD) and related synucleinopathies. However, the exact role of α-syn inclusions in PD pathogenesis remains elusive. This lack of knowledge is mainly due to the absence of optimal α-syn-based animal models that recapitulate the different
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Alzheimer’s genes in microglia: a risk worth investigating Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-20 Ari Sudwarts, Gopal Thinakaran
Despite expressing many key risk genes, the role of microglia in late-onset Alzheimer’s disease pathophysiology is somewhat ambiguous, with various phenotypes reported to be either harmful or protective. Herein, we review some key findings from clinical and animal model investigations, discussing the role of microglial genetics in mediating perturbations from homeostasis. We note that impairment to
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Donald Lowell Price, M.D. In memoriam Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-20 Sangram Sisodia, Philip C. Wong
Dr. Donald L. Price, one of the most prolific and distinguished neuroscientists in the field of Alzheimer’s disease and neurodegeneration, has passed. Don was a pioneer in clinical and experimental neuropathology, a devoted husband, father and grandfather, and a mentor to a legion of scientists who followed him. Don was a quintessential renaissance man who read literature in college and thereafter
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Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-16 Saadia Hasan, Michael S. Fernandopulle, Stewart W. Humble, Ashley M. Frankenfield, Haorong Li, Ryan Prestil, Kory R. Johnson, Brent J. Ryan, Richard Wade-Martins, Michael E. Ward, Ling Hao
Progranulin (PGRN) is a lysosomal glycoprotein implicated in various neurodegenerative diseases, including frontotemporal dementia and neuronal ceroid lipofuscinosis. Over 70 mutations discovered in the GRN gene all result in reduced expression of the PGRN protein. Genetic and functional studies point toward a regulatory role for PGRN in lysosome functions. However, the detailed molecular function
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Roles of peripheral lipoproteins and cholesteryl ester transfer protein in the vascular contributions to cognitive impairment and dementia Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-16 Tetiana Poliakova, Cheryl L. Wellington
This narrative review focuses on the role of cholesteryl ester transfer protein (CETP) and peripheral lipoproteins in the vascular contributions to cognitive impairment and dementia (VCID). Humans have a peripheral lipoprotein profile where low-density lipoproteins (LDL) represent the dominant lipoprotein fraction and high-density lipoproteins (HDL) represent a minor lipoprotein fraction. Elevated
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Altered plasma protein profiles in genetic FTD – a GENFI study Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-15 Abbe Ullgren, Linn Öijerstedt, Jennie Olofsson, Sofia Bergström, Julia Remnestål, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Barbara Borroni, Raquel Sanchez-Valle, Fermin Moreno, Robert Laforce, Matthis Synofzik, Daniela Galimberti, James B. Rowe, Mario Masellis, Maria Carmela Tartaglia, Elizabeth Finger, Rik Vandenberghe, Alexandre de Mendonça, Pietro Tirabosch, Isabel Santana, Simon Ducharme
Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Blood samples from 693 participants
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α-Synuclein serine129 phosphorylation – the physiology of pathology Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-13 Nagendran Ramalingam, Ulf Dettmer
The study that found phospho-serine129 in the Parkinson’s-linked protein alpha-synuclein over two decades ago proposed a physiological role in regulating protein function, but this notion was neglected when alpha-synuclein serine129 phosphorylation was identified in Lewy bodies/neurites, the hallmark pathology of synucleinopathies. Recent work suggests that both are relevant: pathological phospho-serine129
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Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-11 Martin T. Henrich, Wolfgang H. Oertel, D. James Surmeier, Fanni F. Geibl
Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson’s disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment
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Simple model systems reveal conserved mechanisms of Alzheimer’s disease and related tauopathies Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-10 Yuwei Jiang, Lesley T. MacNeil
The lack of effective therapies that slow the progression of Alzheimer’s disease (AD) and related tauopathies highlights the need for a more comprehensive understanding of the fundamental cellular mechanisms underlying these diseases. Model organisms, including yeast, worms, and flies, provide simple systems with which to investigate the mechanisms of disease. The evolutionary conservation of cellular
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Correction: Drug development targeting degeneration of the basal forebrain cholinergic system: its time has come Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-09 John J. Alam, Ralph A. Nixon
Molecular Neurodegeneration (2023) 18:74 https://doi.org/10.1186/s13024-023-00663-y In the original article [1] the following statement of funding acknowledgement was mistakenly omitted: “Preclinical studies have been supported by NIH grants P01AG017617 and R01AG062376 grants to RAN.” Authors and Affiliations CervoMed Inc, 20 Park Plaza, Suite 424, Boston, MA, 02116, USA John J. Alam Center for Dementia
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Peptide-based approaches to directly target alpha-synuclein in Parkinson’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-09 Scott G. Allen, Richard M. Meade, Lucy L. White Stenner, Jody M. Mason
Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large for inhibition by small molecules, and inaccessible to larger biologics. In the past two decades, evidence associating the misfolding and aggregation of alpha-synuclein strongly implicates this protein in disease onset and progression of Parkinson’s disease
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Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-08 Yige Huang, Bangyan Liu, Subhash C. Sinha, Sadaf Amin, Li Gan
DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through
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cGAS-STING triggers inflammaging-associated neurodegeneration Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-23 José M. Izquierdo
In their recent article in Nature, Gulen et al. [1] established the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway as a regulatory driver of inflammaging-associated neurodegeneration in mice. Pharmacological blockade of this pathway in aged mice prevented inflammaging and improved cognitive and motor performance. In the same vein, chemical intervention attenuated a toxic
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Genome-wide analyses identify NEAT1 as genetic modifier of age at onset of amyotrophic lateral sclerosis Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-23 Chunyu Li, Qianqian Wei, Yanbing Hou, Junyu Lin, Ruwei Ou, Lingyu Zhang, Qirui Jiang, Yi Xiao, Kuncheng Liu, Xueping Chen, TianMi Yang, Wei Song, Bi Zhao, Ying Wu, Huifang Shang
Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown. To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox
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Mechanisms of ARIA: is it time to focus on the unique immune environment of the neurovascular unit? Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-20 Kate E. Foley, Erica M. Weekman, Donna M. Wilcock
Microhemorrhages as a consequence of anti-Ab immunotherapy were first identified over 20 years ago in a single page report in Science by Pfeifer et al. [1]. Following on from that, both Wilcock and Racke reported microhemorrhages in 2004 and 2005 respectively, in different animal models and with different Ab antibodies [2, 3]. When vasogenic edema and microhemorrhages were identified in clinical trials
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Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-19 Manling Xie, Praveen N. Pallegar, Sebastian Parusel, Aivi T. Nguyen, Long-Jun Wu
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous
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Drug development targeting degeneration of the basal forebrain cholinergic system: its time has come Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-04 John J. Alam, Ralph A. Nixon
Recent advances in understanding the pathogenic mechanisms underlying basal forebrain cholinergic (BFC) neuronal degeneration and MRI-based studies provide insight on the contribution of such degeneration at various stages of Alzheimer’s disease (AD) and related dementias and have renewed interest in disease-modifying approaches to treat BFC degeneration. Herein we comment on two recent related publications
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Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-03 Ken Uekawa, Yorito Hattori, Sung Ji Ahn, James Seo, Nicole Casey, Antoine Anfray, Ping Zhou, Wenjie Luo, Josef Anrather, Laibaik Park, Costantino Iadecola
Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer’s disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages
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Correction: Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-02 Pierre De Rossi, Virginie Buggia-Prévot, Benjamin L. L. Clayton, Jared B. Vasquez, Carson van Sanford, Robert J. Andrew, Ruben Lesnick, Alexandra Botté, Carole Deyts, Someya Salem, Eshaan Rao, Richard C. Rice, Angèle Parent, Satyabrata Kar, Brian Popko, Peter Pytel, Steven Estus, Gopal Thinakaran
Correction: Mol Neurodegeneration 11, 59 (2016) https://doi.org/10.1186/s13024-016-0124-1 Correction The original article [1] contains an error whereby, in the Methods section on page 3, the last sentence on the left column (continuing to the right column) reads: ‘D7-BIN1 reactions used the same exon 5 sense primer and a junctional antisense primer, 5’-GCTTTCTCAAGCAGCGAGAC-3’, corresponding to the
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TDP-43 pathology is associated with increased tau burdens and seeding Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-30 Sandra O. Tomé, Grigoria Tsaka, Alicja Ronisz, Simona Ospitalieri, Klara Gawor, Luis Aragão Gomes, Markus Otto, Christine A. F. von Arnim, Philip Van Damme, Ludo Van Den Bosch, Estifanos Ghebremedhin, Celeste Laureyssen, Kristel Sleegers, Rik Vandenberghe, Frederic Rousseau, Joost Schymkowitz, Dietmar Rudolf Thal
Most Alzheimer’s Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-β plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD
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A microglial activity state biomarker panel differentiates FTD-granulin and Alzheimer’s disease patients from controls Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-29 Ida Pesämaa, Stephan A. Müller, Sophie Robinson, Alana Darcher, Dominik Paquet, Henrik Zetterberg, Stefan F. Lichtenthaler, Christian Haass
With the emergence of microglia-modulating therapies there is an urgent need for reliable biomarkers to evaluate microglial activation states. Using mouse models and human induced pluripotent stem cell-derived microglia (hiMGL), genetically modified to yield the most opposite homeostatic (TREM2-knockout) and disease-associated (GRN-knockout) states, we identified microglia activity-dependent markers
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Correction: Targeted degradation of ⍺-synuclein aggregates in Parkinson’s disease using the AUTOTAC technology Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-29 Jihoon Lee, Ki Woon Sung, Eun-Jin Bae, Dabin Yoon, Dasarang Kim, Jin Saem Lee, Da-ha Park, Daniel Youngjae Park, Su Ran Mun, Soon Chul Kwon, Hye Yeon Kim, Joo-Ok Min, Seung-Jae Lee, Young Ho Suh, Yong Tae Kwon
Molecular Neurodegeneration (2023) 18:41 https://doi.org/10.1186/s13024-023-00630-7. The original article [1] contained errors in the Funding section. The correct Funding information can be viewed ahead: Funding This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Ministry of Science, ICT and Future Planning (MSIP) (NRF-2020R1A5A1019023 to Y.T.K., NRF-2021R1A2B5B03002614
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The Q/R editing site of AMPA receptor GluA2 subunit acts as an epigenetic switch regulating dendritic spines, neurodegeneration and cognitive deficits in Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-28 Amanda L. Wright, Lyndsey M. Konen, Bruce G. Mockett, Gary P. Morris, Anurag Singh, Lisseth Estefania Burbano, Luke Milham, Monica Hoang, Raphael Zinn, Rose Chesworth, Richard P. Tan, Gordon A. Royle, Ian Clark, Steven Petrou, Wickliffe C. Abraham, Bryce Vissel
RNA editing at the Q/R site of GluA2 occurs with ~99% efficiency in the healthy brain, so that the majority of AMPARs contain GluA2(R) instead of the exonically encoded GluA2(Q). Reduced Q/R site editing infcreases AMPA receptor calcium permeability and leads to dendritic spine loss, neurodegeneration, seizures and learning impairments. Furthermore, GluA2 Q/R site editing is impaired in Alzheimer’s
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Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-27 Arpan G. Mazumder, Amélie M. Julé, Daniel Sun
The optic nerve is an important tissue in glaucoma and the unmyelinated nerve head region remains an important site of many early neurodegenerative changes. In both humans and mice, astrocytes constitute the major glial cell type in the region, and in glaucoma they become reactive, influencing the optic nerve head (ONH) microenvironment and disease outcome. Despite recognizing their importance in the
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BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-26 Margaret E. Maes, Ryan J. Donahue, Cassandra L. Schlamp, Olivia J. Marola, Richard T. Libby, Robert W. Nickells
Pro-apoptotic BAX is a central mediator of retinal ganglion cell (RGC) death after optic nerve damage. BAX activation occurs in two stages including translocation of latent BAX to the mitochondrial outer membrane (MOM) and then permeabilization of the MOM to facilitate the release of apoptotic signaling molecules. As a critical component of RGC death, BAX is an attractive target for neuroprotective
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News & views: anti-amyloid antibodies and novel emerging approaches to Alzheimer’s disease in 2023 Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-25 Sam Gandy
Alzheimer’s disease (AD) was described over a century ago as a disease of dementia with the presence of amyloid and tau pathologies [1], but the past year has seen the first clear evidence that effective disease-modifying anti-amyloid antibody (AAA) therapies are possible. Both aducanumab [2] (from Biogen) and lecanemab [3, 4] (from an Eisai-Biogen collaboration) earned accelerated approval from the
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Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-21 Jonathan R. Soucy, Erika A. Aguzzi, Julie Cho, Michael James Gilhooley, Casey Keuthan, Ziming Luo, Aboozar Monavarfeshani, Meher A. Saleem, Xue-Wei Wang, Juilette Wohlschlegel, Petr Baranov, Adriana Di Polo, Brad Fortune, Kimberly K. Gokoffski, Jeffrey L. Goldberg, William Guido, Alex L. Kolodkin, Carol A. Mason, Yvonne Ou, Thomas A. Reh, Ahmara G. Ross, Brian C. Samuels, Derek Welsbie, Donald J. Zack
Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system’s limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be
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The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-19 Jun Yup Lee, Dylan J Harney, Jonathan D Teo, John B Kwok, Greg T. Sutherland, Mark Larance, Anthony S Don
The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal
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Regulation of the hippocampal translatome by Apoer2-ICD release Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-19 Catherine R. Wasser, Gordon C. Werthmann, Eric M. Hall, Kristina Kuhbandner, Connie H. Wong, Murat S. Durakoglugil, Joachim Herz
ApoE4, the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-β toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset
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Amyloid fibril proteomics of AD brains reveals modifiers of aggregation and toxicity Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-14 Arun Upadhyay, Deepak Chhangani, Nalini R. Rao, Julia Kofler, Robert Vassar, Diego E. Rincon-Limas, Jeffrey N. Savas
The accumulation of amyloid beta (Aβ) peptides in fibrils is prerequisite for Alzheimer’s disease (AD). Our understanding of the proteins that promote Aβ fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts. To investigate how amyloid fibrils form and cause neurotoxicity in AD brain, we developed a robust biochemical
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Tracking reactive astrogliosis in autosomal dominant and sporadic Alzheimer’s disease with multi-modal PET and plasma GFAP Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-12 Konstantinos Chiotis, Charlotte Johansson, Elena Rodriguez-Vieitez, Nicholas J. Ashton, Kaj Blennow, Henrik Zetterberg, Caroline Graff, Agneta Nordberg
Plasma assays for the detection of Alzheimer’s disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-β burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer 11C-Deuterium-L-Deprenyl (11C-DED)
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Amyloid-β (Aβ) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer’s disease mice Mol. Neurodegener. (IF 15.1) Pub Date : 2023-08-30 Xavier Taylor, Isaiah M. Clark, Griffin J. Fitzgerald, Herold Oluoch, Justin T. Hole, Ronald B. DeMattos, Yaming Wang, Feng Pan
Amyloid-related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events resulting from pathological changes in the cerebral vasculature during several recent anti-amyloid-β (Aβ) immunotherapy trials. However, the precise cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)-mediated alterations in vascular
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Translation dysregulation in neurodegenerative diseases: a focus on ALS Mol. Neurodegener. (IF 15.1) Pub Date : 2023-08-25 Shaopeng Wang, Shuying Sun
RNA translation is tightly controlled in eukaryotic cells to regulate gene expression and maintain proteome homeostasis. RNA binding proteins, translation factors, and cell signaling pathways all modulate the translation process. Defective translation is involved in multiple neurological diseases including amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder and poses
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TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains Mol. Neurodegener. (IF 15.1) Pub Date : 2023-08-21 Virginia Estades Ayuso, Sarah Pickles, Tiffany Todd, Mei Yue, Karen Jansen-West, Yuping Song, Jesús González Bejarano, Bailey Rawlinson, Michael DeTure, Neill R. Graff-Radford, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Dennis W. Dickson, Keith A. Josephs, Leonard Petrucelli, Mercedes Prudencio
Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction
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Oleoylethanolamide facilitates PPARα and TFEB signaling and attenuates Aβ pathology in a mouse model of Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-08-15 Michele M. Comerota, Manasee Gedam, Wen Xiong, Feng Jin, Lisheng Deng, Meng C. Wang, Jin Wang, Hui Zheng
Age is the strongest risk factor for the development of Alzheimer’s disease (AD). Besides the pathological hallmarks of β-amyloid (Aβ) plaques and neurofibrillary tangles, emerging evidence demonstrates a critical role of microglia and neuroinflammation in AD pathogenesis. Oleoylethanolamide (OEA) is an endogenous lipid amide that has been shown to promote lifespan and healthspan in C. elegans through
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Current views on meningeal lymphatics and immunity in aging and Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-08-14 Shanon Rego, Guadalupe Sanchez, Sandro Da Mesquita
Alzheimer’s disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in the brain. These phenomena are accompanied by exacerbated inflammation and marked neuronal loss, which altogether contribute to accelerated cognitive decline. The multifactorial nature of AD, allied to our still limited knowledge of
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TMEM106B aggregation in neurodegenerative diseases: linking genetics to function Mol. Neurodegener. (IF 15.1) Pub Date : 2023-08-10 Hai-Shan Jiao, Peng Yuan, Jin-Tai Yu
Mutations of the gene TMEM106B are risk factors for diverse neurodegenerative diseases. Previous understanding of the underlying mechanism focused on the impairment of lysosome biogenesis caused by TMEM106B loss-of-function. However, mutations in TMEM106B increase its expression level, thus the molecular process linking these mutations to the apparent disruption in TMEM106B function remains mysterious
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Specific detection of tau seeding activity in Alzheimer’s disease using rationally designed biosensor cells Mol. Neurodegener. (IF 15.1) Pub Date : 2023-08-08 Aurelien Lathuiliere, Youhwa Jo, Romain Perbet, Cameron Donahue, Caitlin Commins, Noé Quittot, Zhanyun Fan, Rachel E. Bennett, Bradley T. Hyman
The prion-like propagation of tau in neurodegenerative disorders implies that misfolded pathological tau can recruit the normal protein and template its aggregation. Here, we report the methods for the development of sensitive biosensor cell lines for the detection of tau seeding activity. We performed the rational design of novel tau probes based on the current structural knowledge of pathological
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Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases Mol. Neurodegener. (IF 15.1) Pub Date : 2023-08-07 Siwei Chu, Xinyi Xie, Carla Payan, Ursula Stochaj
The AAA+ ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part of a large network, VCP collaborates with many cofactors to ensure proteostasis under normal, stress, and disease conditions. A large number of mutations have revealed the importance of VCP for human health. In particular, VCP facilitates the dismantling of
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VPS35 and α-Synuclein fail to interact to modulate neurodegeneration in rodent models of Parkinson’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-08-04 Xi Chen, Elpida Tsika, Nathan Levine, Darren J. Moore
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene cause late-onset, autosomal dominant Parkinson’s disease (PD), with a single missense mutation (Asp620Asn, D620N) known to segregate with disease in families with PD. The VPS35 gene encodes a core component of the retromer complex, involved in the endosomal sorting and recycling of transmembrane cargo proteins. VPS35-linked PD is clinically
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Optimizing detection of Alzheimer’s disease in mild cognitive impairment: a 4-year biomarker study of mild behavioral impairment in ADNI and MEMENTO Mol. Neurodegener. (IF 15.1) Pub Date : 2023-07-29 Zahinoor Ismail, Rebeca Leon, Byron Creese, Clive Ballard, Philippe Robert, Eric E. Smith
Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding
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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases Mol. Neurodegener. (IF 15.1) Pub Date : 2023-07-20 Sen Yang, Jung Hyun Park, Hui-Chen Lu
Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions
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Quantitative proteomics of cerebrospinal fluid from African Americans and Caucasians reveals shared and divergent changes in Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-07-19 Erica S. Modeste, Lingyan Ping, Caroline M. Watson, Duc M. Duong, Eric B. Dammer, Erik C. B. Johnson, Blaine R. Roberts, James J. Lah, Allan I. Levey, Nicholas T. Seyfried
Despite being twice as likely to get Alzheimer’s disease (AD), African Americans have been grossly underrepresented in AD research. While emerging evidence indicates that African Americans with AD have lower cerebrospinal fluid (CSF) levels of Tau compared to Caucasians, other differences in AD CSF biomarkers have not been fully elucidated. Here, we performed unbiased proteomic profiling of CSF from
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ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-07-12 Yingbin Lin, Anlan Lin, Lili Cai, Weibin Huang, Shanzhi Yan, Yuanxiang Wei, Xinglin Ruan, Wenting Fang, Xiaoman Dai, Jinbo Cheng, Jie Zhang, Wanjin Chen, Qinyong Ye, Xiaochun Chen, Jing Zhang
Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer’s disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood. We
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Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-07-11 Yasuteru Inoue, Francis Shue, Guojun Bu, Takahisa Kanekiyo
Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer’s disease
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The gut microbiome regulates astrocyte reaction to Aβ amyloidosis through microglial dependent and independent mechanisms Mol. Neurodegener. (IF 15.1) Pub Date : 2023-07-06 Sidhanth Chandra, Antonio Di Meco, Hemraj B. Dodiya, Jelena Popovic, Leah K. Cuddy, Ian Q. Weigle, Xiaoqiong Zhang, Katherine Sadleir, Sangram S. Sisodia, Robert Vassar
Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aβ) plaques and proinflammatory microglial phenotype in male APPPS1-21 mice. However, the effect of GMB perturbation on astrocyte phenotypes and microglial-astrocyte communication in the context of amyloidosis has not been examined. To study whether the GMB modulates astrocyte
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Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-07-04 Yogesh Singh, Christoph Trautwein, Joan Romani, Madhuri S. Salker, Peter H. Neckel, Isabel Fraccaroli, Mahkameh Abeditashi, Nils Woerner, Jakob Admard, Achal Dhariwal, Morten K. D. Dueholm, Karl-Herbert Schäfer, Florian Lang, Daniel E. Otzen, Hilal A. Lashuel, Olaf Riess, Nicolas Casadei
Braak’s hypothesis states that sporadic Parkinson’s disease (PD) follows a specific progression of pathology from the peripheral to the central nervous system, and this progression can be monitored by detecting the accumulation of alpha-Synuclein (α-Syn) protein. Consequently, there is growing interest in understanding how the gut (commensal) microbiome can regulate α-Syn accumulation, as this could
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Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-07-03 Shan P. Yu, Michael Q. Jiang, Seong S. Shim, Soheila Pourkhodadad, Ling Wei
Stroke and late-onset Alzheimer’s disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background
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Anti-amyloid therapies for Alzheimer disease: finally, good news for patients Mol. Neurodegener. (IF 15.1) Pub Date : 2023-06-28 Vijay K. Ramanan, Gregory S. Day
Recent advances in Alzheimer disease (AD) therapeutics represent a step in the right direction for patients with AD. In recent phase 3 trials for early symptomatic AD, lecanemab (CLARITY-AD) and donanemab (TRAILBLAZER-ALZ2) led to slowing of cognitive and functional decline, and positive alterations on disease-specific biomarkers [1, 2]. The substantial complexities of these new therapies highlight
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Targeted degradation of ⍺-synuclein aggregates in Parkinson’s disease using the AUTOTAC technology Mol. Neurodegener. (IF 15.1) Pub Date : 2023-06-24 Jihoon Lee, Ki Woon Sung, Eun-Jin Bae, Dabin Yoon, Dasarang Kim, Jin Saem Lee, Da-ha Park, Daniel Youngjae Park, Su Ran Mun, Soon Chul Kwon, Hye Yeon Kim, Joo-Ok Min, Seung-Jae Lee, Young Ho Suh, Yong Tae Kwon
There are currently no disease-modifying therapeutics for Parkinson’s disease (PD). Although extensive efforts were undertaken to develop therapeutic approaches to delay the symptoms of PD, untreated α-synuclein (α-syn) aggregates cause cellular toxicity and stimulate further disease progression. PROTAC (Proteolysis-Targeting Chimera) has drawn attention as a therapeutic modality to target α-syn. However
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A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores Mol. Neurodegener. (IF 15.1) Pub Date : 2023-06-22 Moonil Kang, Ting Fang Alvin Ang, Sherral A. Devine, Richard Sherva, Shubhabrata Mukherjee, Emily H. Trittschuh, Laura E. Gibbons, Phoebe Scollard, Michael Lee, Seo-Eun Choi, Brandon Klinedinst, Connie Nakano, Logan C. Dumitrescu, Alaina Durant, Timothy J. Hohman, Michael L. Cuccaro, Andrew J. Saykin, Walter A. Kukull, David A. Bennett, Li-San Wang, Richard P. Mayeux, Jonathan L. Haines, Margaret A
More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function
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Sex specific molecular networks and key drivers of Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-06-20 Lei Guo, Jiqing Cao, Jianwei Hou, Yonghe Li, Min Huang, Li Zhu, Larry Zhang, Yeji Lee, Mariana Lemos Duarte, Xianxiao Zhou, Minghui Wang, Chia-Chen Liu, Yuka Martens, Michael Chao, Alison Goate, Guojun Bu, Vahram Haroutunian, Dongming Cai, Bin Zhang
Alzheimer’s disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate
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Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate Mol. Neurodegener. (IF 15.1) Pub Date : 2023-06-06 Michal Nemergut, Sérgio M. Marques, Lukas Uhrik, Tereza Vanova, Marketa Nezvedova, Darshak Chandulal Gadara, Durga Jha, Jan Tulis, Veronika Novakova, Joan Planas-Iglesias, Antonin Kunka, Anthony Legrand, Hana Hribkova, Veronika Pospisilova, Jiri Sedmik, Jan Raska, Zbynek Prokop, Jiri Damborsky, Dasa Bohaciakova, Zdenek Spacil, Lenka Hernychova, David Bednar, Martin Marek
Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer’s Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown. Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray
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The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap Mol. Neurodegener. (IF 15.1) Pub Date : 2023-06-05 Keenan A. Walker, Lydia M. Le Page, Niccolò Terrando, Michael R. Duggan, Michael T. Heneka, Brianne M. Bettcher
Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer’s disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory
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Resistant and Resilient mutations in protection against familial Alzheimer’s disease: learning from nature Mol. Neurodegener. (IF 15.1) Pub Date : 2023-06-01 Diego Sepulveda-Falla
Alzheimer’s disease (AD) is the most common cause of dementia and a multifactorial disorder affecting around 50 million people worldwide. It is characterized by progressive cognitive impairment eventually leading to death. Postmortem findings of AD pathological hallmarks remain as the main criteria for a definitive diagnosis, despite considerable advances in diagnostic biomarkers. The identification
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Looking for answers far away from the soma—the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS Mol. Neurodegener. (IF 15.1) Pub Date : 2023-05-31 Ariel Ionescu, Topaz Altman, Eran Perlson
Axon degeneration and Neuromuscular Junction (NMJ) disruption are key pathologies in the fatal neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Despite accumulating evidence that axons and NMJs are impacted at a very early stage of the disease, current knowledge about the mechanisms leading to their degeneration remains elusive. Cytoplasmic mislocalization and accumulation of the protein