Defective mitochondrial and lysosomal trafficking in chorea-acanthocytosis is independent of Src-kinase signaling Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-08-03 Hannes Glaß, Arun Pal, Peter Reinhardt, Jared Sterneckert, Florian Wegner, Alexander Storch, Andreas Hermann
Mutations in the VPS13A gene leading to depletion of chorein protein are causative for Chorea Acanthocytosis (ChAc), a rare devastating disease, which is characterized by neurodegeneration mainly affecting the basal ganglia as well as deformation of erythrocytes. Studies on patient blood samples highlighted a dysregulation of Actin cytoskeleton caused by downregulation of the PI3K pathway and hyper-activation of Lyn-kinase, but to what extent these mechanisms are present and relevant in the affected neurons remains elusive. We studied the effects of the absence of chorein protein on the morphology and trafficking of lysosomal and mitochondrial compartments in ChAc patient-specific induced pluripotent stem cell-derived medium spiny neurons (MSNs). Numbers of both organelle types were reduced in ChAc MSNs. Mitochondrial length was shortened and their membrane potential showed significant hyperpolarization. In contrast to previous studies, showing Lyn kinase dependency of ChAc-associated pathological events in erythrocytes, pharmacological studies demonstrate that the impairment of mitochondria and lysosomes are independent of Lyn kinase activity. These data suggest that impairment in mitochondrial and lysosomal morphologies in MSNs is not mediated by a dysregulation of Lyn kinase and thus the pathological pathways in ChAc might be – at least in part – cell-type specific.
The effect of Jun dimerization on neurite outgrowth and motif binding Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-08-03 Matt C. Danzi, Saloni T. Mehta, Kireeti Dulla, Giulia Zunino, Daniel J. Cooper, John L. Bixby, Vance P. Lemmon
Axon regeneration is a necessary step toward functional recovery after spinal cord injury. The AP-1 transcription factor c-Jun has long been known to play an important role in directing the transcriptional response of Dorsal Root Ganglion (DRG) neurons to peripheral axotomy that results in successful axon regeneration. Here we performed ChIPseq for Jun in mouse DRG neurons after a sciatic nerve crush or sham surgery in order to measure the changes in Jun's DNA binding in response to peripheral axotomy. We found that the majority of Jun's injury-responsive changes in DNA binding occur at putative enhancer elements, rather than proximal to transcription start sites. We also used a series of single polypeptide chain tandem transcription factors to test the effects of different Jun-containing dimers on neurite outgrowth in DRG, cortical and hippocampal neurons. These experiments demonstrated that dimers composed of Jun and Atf3 promoted neurite outgrowth in rat CNS neurons as well as mouse DRG neurons. Our work provides new insight into the mechanisms underlying Jun's role in axon regeneration.
The ferroxidase ceruloplasmin influences Reelin processing, cofilin phosphorylation and neuronal organization in the developing brain Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-08-02 Philippe Ducharme, Juan G. Zarruk, Samuel David, Joanne Paquin
Ceruloplasmin (Cp) is an important extracellular regulator of iron metabolism. We showed previously that it stimulates Reelin proteolytic processing and cell aggregation in cultures of developing neurons. Reelin is a secreted protein required for the correct positioning of neurons in the brain. It is cleaved in vivo into N-terminally-derived 300K and 180K fragments through incompletely known mechanisms. One of Reelin signaling targets is the actin-binding protein cofilin, the phosphorylation of which is diminished in Reelin-deficient mice. This work looked for in vivo evidence of a relationship between Cp, Reelin and neuronal organization during brain development by analyzing wild-type and Cp-null mice. Cp as well as the full-length, 300K and 180K Reelin species appeared together in wild-type brains at embryonic day (E) 12.5 by immunoblotting. In wild-type compared to Cp-null brains, there was more 300K Reelin from E12.5 to E17.5, a period characterized by extensive, radially directed neuronal migration in the cerebral cortex. Immunofluorescence labeling of tissue sections at E16.5 revealed the localization of Cp with radial glia and meningeal cells adjacent to Reelin-producing Cajal-Retzius neurons, underlining the proximity of Cp and Reelin. Cofilin phosphorylation was seen starting at E10.5–E12.5 and lasted longer until postnatal day 7 in wild-type than Cp-null mice. Finally, using CUX1 as a marker revealed defective accumulation of neurons in layers II/III in neonatal and adult Cp-null mice. These results combined with our earlier work point to a potentially new role of Cp in Reelin processing and signaling and neuronal organization in the cerebral cortex in vivo.
Changes in synaptic AMPA receptor concentration and composition in chronic temporal lobe epilepsy Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-07-29 Daniel L. Egbenya, Suleman Hussain, Yi-Chen Lai, Jun Xia, Anne E. Anderson, Svend Davanger
Excitotoxicity caused by excessive stimulation of glutamate receptors, resulting in pathologically increased Ca2+-concentrations, is a decisive factor in neurodegenerative diseases. We investigated long-term changes in synaptic contents of AMPA receptor subunits that play important roles in calcium regulation in chronic epilepsy. Such plastic changes may be either adaptive or detrimental. We used a kainic acid (KA)-based rat model of chronic temporal lobe epilepsy (TLE). We found significant reductions in the concentration of the AMPA receptor subunits GluA1 and GluA2, and the NMDA receptor subunit NR2B. The relative size of GluA1 and GluA2 reductions were almost identical, at 28% and 27%, respectively. In order to determine whether the synaptic reduction of the AMPA receptor subunits actually reflected the pool of receptors present along the postsynaptic density (PSD), as opposed to cytoplasmic or extrasynaptic pools, we performed postembedding immunogold electron microscopy (EM) of GluA1 and GluA2 in Schaffer collateral synapses in the hippocampal CA1 area. We found significant reductions, at 32% and 52% of GluA1 and GluA2 subunits, respectively, along the PSD, indicating that these synapses undergo lasting changes in glutamatergic neurotransmission during chronic TLE. When compared to the overall concentration and composition of AMPA receptors expressed in the brain, there was a relative increase in GluA2-lacking AMPA receptor subunits following chronic epilepsy. These changes in synaptic AMPA receptor subunits may possibly contribute to further aggravate the excitotoxic vulnerability of the neurons as well as have significant implications for hippocampal cognitive functions.
Physiological signature of a novel potentiator of AMPA receptor signalling Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-07-22 Blanka R. Szulc, Stephen T. Hilton, Arnaud J. Ruiz
We have synthesized a novel small molecule based on the pyrrolidinone–containing core structure of clausenamide, which is a candidate anti–dementia drug. The synthetic route yielded multi–gram quantities of an isomeric racemate mixture in a short number of steps. When tested in hippocampal slices from young adult rats the compound enhanced AMPA receptor–mediated signalling at mossy fibre synapses, and potentiated inward currents evoked by local application of l–glutamate onto CA3 pyramidal neurons. It facilitated the induction of mossy fibre LTP, but the magnitude of potentiation was smaller than that observed in untreated slices. The racemic mixture was separated and it was shown that only the (−) enantiomer was active. Toxicity analysis indicated that cell lines tolerated the compound at concentrations well above those enhancing synaptic transmission. Our results unveil a small molecule whose physiological signature resembles that of a potent nootropic drug.
EphBs and ephrin-Bs: Trans-synaptic organizers of synapse development and function Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-07-19 Nathan Henderson, Matthew B. Dalva
Synapses are specialized cell-cell junctions that underlie the function of neural circuits by mediating communication between neurons. Both the formation and function of synapses require tight coordination between pre- and post-synaptic neurons. Trans-synaptic organizing molecules are important mediators of such signaling. Here we discuss how the EphB and ephrin-B families of trans-synaptic organizing proteins direct synapse formation during early development and regulate synaptic function and plasticity at mature synapses. Finally, we highlight recent evidence linking the synaptic organizing role of EphBs and ephrin-Bs to diseases of maladaptive synaptic function and plasticity.
Class 4 Semaphorins and Plexin-B receptors regulate GABAergic and glutamatergic synapse development in the mammalian hippocampus Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-07-04 Jacqueline E. McDermott, Dena Goldblatt, Suzanne Paradis
To understand how proper circuit formation and function is established in the mammalian brain, it is necessary to define the genes and signaling pathways that instruct excitatory and inhibitory synapse development. We previously demonstrated that the ligand-receptor pair, Sema4D and Plexin-B1, regulates inhibitory synapse development on an unprecedentedly fast time-scale while having no effect on excitatory synapse development. Here, we report previously undescribed synaptogenic roles for Sema4A and Plexin-B2 and provide new insight into Sema4D and Plexin-B1 regulation of synapse development in rodent hippocampus. First, we show that Sema4a, Sema4d, Plxnb1, and Plxnb2 have distinct and overlapping expression patterns in neurons and glia in the developing hippocampus. Second, we describe a requirement for Plexin-B1 in both the presynaptic axon of inhibitory interneurons as well as the postsynaptic dendrites of excitatory neurons for Sema4D-dependent inhibitory synapse development. Third, we define a new synaptogenic activity for Sema4A in mediating inhibitory and excitatory synapse development. Specifically, we demonstrate that Sema4A signals through the same pathway as Sema4D, via the postsynaptic Plexin-B1 receptor, to promote inhibitory synapse development. However, Sema4A also signals through the Plexin-B2 receptor to promote excitatory synapse development. Our results shed new light on the molecular cues that promote the development of either inhibitory or excitatory synapses in the mammalian hippocampus.
Involvement of l-afadin, but not s-afadin, in the formation of puncta adherentia junctions of hippocampal synapses Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-06-30 Tomohiko Maruo, Shotaro Sakakibara, Muneaki Miyata, Yu Itoh, Souichi Kurita, Kenji Mandai, Takuya Sasaki, Yoshimi Takai
A hippocampal mossy fiber synapse has a complex structure in which presynaptic boutons attach to the dendritic trunk by puncta adherentia junctions (PAJs) and wrap multiply-branched spines, forming synaptic junctions. It was previously shown that afadin regulates the formation of the PAJs cooperatively with nectin-1, nectin-3, and N-cadherin. Afadin is a nectin-binding protein with two splice variants, l-afadin and s-afadin: l-afadin has an actin filament-binding domain, whereas s-afadin lacks it. It remains unknown which variant is involved in the formation of the PAJs or how afadin regulates it. We showed here that re-expression of l-afadin, but not s-afadin, in the afadin-deficient cultured hippocampal neurons in which the PAJ-like structure was disrupted, restored this structure as estimated by the accumulation of N-cadherin and αΝ-catenin. The l-afadin mutant, in which the actin filament-binding domain was deleted, or the l-afadin mutant, in which the αΝ-catenin-binding domain was deleted, did not restore the PAJ-like structure. These results indicate that l-afadin, but not s-afadin, regulates the formation of the hippocampal synapse PAJ-like structure through the binding to actin filaments and αN-catenin. We further found here that l-afadin bound αN-catenin, but not γ-catenin, whereas s-afadin bound γ-catenin, but hardly αN-catenin. These results suggest that the inability of s-afadin to form the hippocampal synapse PAJ-like structure is due to its inability to efficiently bind αN-catenin.
Partial loss of ATP13A2 causes selective gliosis independent of robust lipofuscinosis Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-06-01 Sruti Rayaprolu, Yasin B. Seven, John Howard, Colin Duffy, Marcelle Altshuler, Christina Moloney, Benoit I. Giasson, Jada Lewis
Loss-of-function mutations in ATP13A2 are associated with three neurodegenerative diseases: a rare form of Parkinson's disease termed Kufor-Rakeb syndrome (KRS), a lysosomal storage disorder termed neuronal ceroid lipofuscinosis (NCL), and a form of hereditary spastic paraplegia (HSP). Furthermore, recent data suggests that heterozygous carriers of mutations in ATP13A2 may confer risk for the development of Parkinson's disease, similar to the association of mutations in glucocerebrosidase (GBA) with both Parkinson's disease and Gaucher's disease, a lysosomal storage disorder. Mutations in ATP13A2 are generally thought to be loss of function; however, the lack of human autopsy tissue has prevented the field from determining the pathological consequences of losing functional ATP13A2. We and others have previously neuropathologically characterized mice completely lacking murine Atp13a2, demonstrating the presence of lipofuscinosis within the brain – a key feature of NCL, one of the diseases to which ATP13A2 mutations have been linked. To determine if loss of one functional Atp13a2 allele can serve as a risk factor for disease, we have now assessed heterozygous Atp13a2 knockout mice for key features of NCL. In this report, we demonstrate that loss of one functional Atp13a2 allele leads to both microgliosis and astrocytosis in multiple brain regions compared to age-matched controls; however, levels of lipofuscin were only modestly elevated in the cortex of heterozygous Atp13a2 knockout mice over controls. This data suggests the possibility that partial loss of ATP13A2 causes inflammatory changes within the brain which appear to be independent of robust lipofuscinosis. This study suggests that heterozygous loss-of-function mutations in ATP13A2 are likely harmful and indicates that glial involvement in the disease process may be an early event that positions the CNS for subsequent disease development.
Urate mitigates oxidative stress and motor neuron toxicity of astrocytes derived from ALS-linked SOD1G93A mutant mice Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-06-18 Rachit Bakshi, Yuehang Xu, Kaly A. Mueller, Xiqun Chen, Eric Granucci, Sabrina Paganoni, Ghazaleh Sadri-Vakili, Michael A. Schwarzschild
Dominant mutations in an antioxidant enzyme superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease characterized by loss of motor neurons. Oxidative stress has also been linked to many of the neurodegenerative diseases and is likely a central mechanism of motor neuron death in ALS. Astrocytes derived from mutant SOD1G93A mouse models or patients play a significant role in the degeneration of spinal motor neurons in ALS through a non-cell-autonomous process. Here we characterize the neuroprotective effects and mechanisms of urate (a.k.a. uric acid), a major endogenous antioxidant and a biomarker of favorable ALS progression rates, in a cellular model of ALS. Our results demonstrate a significant protective effect of urate against motor neuron injury evoked by mutant astrocytes derived from SOD1G93A mice or hydrogen peroxide induced oxidative stress. Overall, these results implicate astrocyte dependent protective effect of urate in a cellular model of ALS. These findings together with our biomarker data may advance novel targets for treating motor neuron disease.
Identification and characterization of two novel alternatively spliced E2F1 transcripts in the rat CNS Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-06-22 Dan P. Jackson, Jenhao H. Ting, Paul D. Pozniak, Claire Meurice, Stephanie S. Schleidt, Anh Dao, Amy H. Lee, Eva Klinman, Kelly L. Jordan-Sciutto
E2F1 is a transcription factor classically known to regulate G0/G1 to S phase progression in the cell cycle. In addition, E2F1 also regulates a wide range of apoptotic genes and thus has been well studied in the context of neuronal death and neurodegenerative diseases. However, its function and regulation in the mature central nervous system are not well understood. Alternative splicing is a well-conserved post-transcriptional mechanism common in cells of the CNS and is necessary to generate diverse functional modifications to RNA or protein products from genes. Heretofore, physiologically significant alternatively spliced E2F1 transcripts have not been reported. In the present study, we report the identification of two novel alternatively spliced E2F1 transcripts: E2F1b, an E2F1 transcript retaining intron 5, and E2F1c, an E2F1 transcript excluding exon 6. These alternatively spliced transcripts are observed in the brain and neural cell types including neurons, astrocytes, and undifferentiated oligodendrocytes. The expression of these E2F1 transcripts is distinct during maturation of primary hippocampal neuroglial cells. Pharmacologically-induced global translation inhibition with cycloheximide, anisomycin or thapsigargin lead to significantly reduced expression of E2F1a, E2F1b and E2F1c. Conversely, increasing neuronal activity by elevating the concentration of potassium chloride selectively increased the expression of E2F1b. Furthermore, experiments expressing these variants in vitro show the transcripts can be translated to generate a protein product. Taken together, our data suggest that the alternatively spliced E2F1 transcript behave differently than the E2F1a transcript, and our results provide a foundation for future investigation of the function of E2F1 splice variants in the CNS.
Semaphorin 3A as an inhibitive factor for migration of olfactory ensheathing cells through cofilin activation is involved in formation of olfactory nerve layer Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-06-27 Ying Wang, Xiaomei Bao, Shiyang Wu, Xiya Shen, Fan Zhang, Zhaoting Lv, Qian Wu, Changnan Xie, Huitao Liu, Jian Lin, Honglin Teng, Zhihui Huang
Olfactory ensheathing cells (OECs) migrate from olfactory epithelium towards olfactory bulb (OB), contributing to formation of the presumptive olfactory nerve layer during development. However, it remains unclear that molecular mechanism of regulation of OEC migration in OB. In the present study, we found that OECs highly expressed the receptors of semaphorin 3A (Sema3A) in vitro and in vivo, whereas Sema3A displayed a gradient expression pattern with higher in inner layer of OB and lower in outer layer of OB. Furthermore, the collapse assays, Boyden chamber migration assays and single-cell migration assays showed that Sema3A induced the collapse of leading front of OECs and inhibited OEC migration. Thirdly, the leading front of OECs exhibited adaptation in a protein synthesis-independent manner, and endocytosis-dependent manner during Sema3A-induced OEC migration. Finally, Sema3A-induced collapse of leading front was required the decrease of focal adhesion and a retrograde F-actin flow in a cofilin activation-dependent manner. Taken together, these results demonstrate that Sema3A as an inhibitive migratory factor for OEC migration through cofilin activation is involved in the formation of olfactory nerve layer.
Regulation of actin dynamics during structural plasticity of dendritic spines: Signaling messengers and actin-binding proteins Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-07-09 Jelena Borovac, Miquel Bosch, Kenichi Okamoto
Activity-dependent plasticity of synaptic structure and function plays an essential role in neuronal development and in cognitive functions including learning and memory. The formation, maintenance and modulation of dendritic spines are mainly controlled by the dynamics of actin filaments (F-actin) through interaction with various actin-binding proteins (ABPs) and postsynaptic signaling messengers. Induction of long-term potentiation (LTP) triggers a cascade of events involving Ca2+ signaling, intracellular pathways such as cAMP and cGMP, and regulation of ABPs such as CaMKII, Cofilin, Aip1, Arp2/3, α-actinin, Profilin and Drebrin. We review here how these ABPs modulate the rate of assembly, disassembly, stabilization and bundling of F-actin during LTP induction. We highlight the crucial role that CaMKII exerts in both functional and structural plasticity by directly coupling Ca2+ signaling with F-actin dynamics through the β subunit. Moreover, we show how cAMP and cGMP second messengers regulate postsynaptic structural potentiation. Brain disorders such as Alzheimer's disease, schizophrenia or autism, are associated with alterations in the regulation of F-actin dynamics by these ABPs and signaling messengers. Thus, a better understanding of the molecular mechanisms controlling actin cytoskeleton can provide cues for the treatment of these disorders.
Depressed mitochondrial function and electron transport Complex II-mediated H2O2 production in the cortex of type 1 diabetic rodents Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-05-23 Subir Roy Chowdhury, Jelena Djordjevic, Ella Thomson, Darrell R. Smith, Benedict C. Albensi, Paul Fernyhough
Aims Abnormalities in mitochondrial function under diabetic conditions can lead to deficits in function of cortical neurons and their support cells exhibiting a pivotal role in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. We aimed to assess mitochondrial respiration rates and membrane potential or H2O2 generation simultaneously and expression of proteins involved in mitochondrial dynamics, ROS scavenging and AMPK/SIRT/PGC-1α pathway activity in cortex under diabetic conditions. Methods Cortical mitochondria from streptozotocin (STZ)-induced type 1 diabetic rats or mice, and aged-matched controls were used for simultaneous measurements of mitochondrial respiration rates and mitochondrial membrane potential (mtMP) or H2O2 using OROBOROS oxygraph. Measurements of enzymatic activities of respiratory complexes were performed using spectophotometry. Protein levels in cortical mitochondria and homogenates were determined by Western blotting. Results Mitochondrial coupled respiration rates and FCCP-induced uncoupled respiration rates were significantly decreased in mitochondria of cortex of STZ-diabetic rats compared to controls. The mtMP in the presence of ADP was significantly depolarized and succinate-dependent respiration rates and H2O2 were significantly diminished in cortical mitochondria of diabetic animals compared to controls, accompanied with reduced expression of CuZn- and Mn-superoxide dismutase. The enzymatic activities of Complex I, II, and IV and protein levels of certain components of Complex I and II, mitofusin 2 (Mfn2), dynamin-related protein 1 (DRP1), P-AMPK, SIRT2 and PGC-1α were significantly diminished in diabetic cortex. Conclusion Deficits in mitochondrial function, dynamics, and antioxidant capabilities putatively mediated through sub-optimal AMPK/SIRT/PGC-1α signaling, are involved in the development of early sub-clinical neurodegeneration in the cortex under diabetic conditions.
The association of spinophilin with disks large-associated protein 3 (SAPAP3) is regulated by metabotropic glutamate receptor (mGluR) 5 Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-06-14 Cameron W. Morris, Darryl S. Watkins, Asma B. Salek, Michael C. Edler, Anthony J. Baucum
Differential gene regulatory plasticity between upper and lower layer cortical excitatory neurons Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-05-23 Lingling Yang, Liuzeng Chen, Chunlin Cai, Hong Li
Neocortical projection neurons consist of intracortical connected upper layer (UL, layer II–IV) neurons and subcortical connected lower layer (LL, layer V–VI) neurons. Afferent activity from the thalamus regulates layer-specific gene expression during postnatal development, which is critical for the formation of proper neocortical cytoarchitecture. Here, we show that activity-dependent gene regulation is confined to UL cortical neurons, but not LL neurons, and that this distinction is likely due to epigenetic modifications of chromatin. We found that the immediate early genes (IEGs), EGR1 and c-FOS, are downregulated in all cortical laminar layers in the absence of afferent activity in vivo. Transcriptional assays demonstrated that EGR1 and c-FOS are able to bind to the promoters of UL- and LL-specific genes to induce transcription. Furthermore, we discovered that LL neurons express higher levels of heterochromatin markers, such as H3K9m3 and H4K20m3, compared to UL neurons. Our results suggest that differential epigenetic modifications of chromatin is an intrinsic mechanism that underlies the different sensitivities of cortical neurons to activity-dependent gene regulation.
BDNF haploinsufficiency exerts a transient and regionally different influence upon oligodendroglial lineage cells during postnatal development Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-05-18 Madeline Nicholson, Rhiannon J. Wood, Jessica L. Fletcher, Maarten van den Buuse, Simon S. Murray, Junhua Xiao
Brain-Derived Neurotrophic Factor (BDNF) plays important roles in promoting myelination in the developing central nervous system (CNS), however the influence it exerts on oligodendrocyte development in vivo remains unclear. As BDNF knockout mice die in the perinatal period, we undertook a systematic developmental analysis of oligodendroglial lineage cells within multiple CNS regions of BDNF heterozygous (HET) mice. Our data identify that BDNF heterozygosity results in transient reductions in oligodendroglial lineage cell density and progression that are largely restricted to the optic nerve, whereas the corpus callosum, cerebral cortex, basal forebrain and spinal cord white matter tracts are unaffected. In the first two postnatal weeks, BDNF HET mice exhibit reductions in the density of oligodendroglial lineage cells, oligodendrocyte precursor cells (OPCs) and postmitotic oligodendrocytes selectively in the optic nerve, but not in the brain or spinal cord white matter tracts. However, this normalizes later in development. The overall proportion of OPCs and mature oligodendrocytes remains unchanged from P9 to P30 in all CNS regions. This study identifies that BDNF exerts transient effects on oligodendroglial lineage cells selectively in the optic nerve during postnatal development. Taken together, this provides compelling evidence that BDNF haploinsufficiency exerts modest effects upon oligodendroglial cell density and lineage progression in vivo, suggesting its major role is restricted to promoting oligodendrocyte myelination.
Astrocyte elevated gene-1 is a novel regulator of astrogliosis and excitatory amino acid transporter-2 via interplaying with nuclear factor-κB signaling in astrocytes from amyotrophic lateral sclerosis mouse model with hSOD1G93A mutation Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-05-16 Xiang Yin, Shuyu Wang, Yan Qi, Xudong Wang, Hongquan Jiang, Tianhang Wang, Yueqing Yang, Ying Wang, Chunting Zhang, Honglin Feng
AEG-1 has received extensive attention on cancer research. However, little is known about its roles in astrogliosis of Amyotrophic lateral sclerosis (ALS). In this study, we detected AEG-1 expression in hSOD1G93A-positive (mut-SOD1) astrocytes and wild type (wt-SOD1) astrocytes, and intend to elucidate its potential functions in ALS related astrogliosis and the always accompanied dysregulated glutamate clearance. Results showed elevated protein and mRNA levels of AEG-1 in mut-SOD1 astrocytes; Also, NF-κB signaling pathway related proteins and inflammatory cytokines were upregulated in mut-SOD1 astrocytes; AEG-1 knockdown attenuated astrocytes proliferation and pro-inflammatory release; also we found that AEG-1 silence inhibited translocation of p65 from cytoplasma to nuclear, which was associated with inhibited NF-κB signaling. Besides, excitatory amino acid transporter-2 (EAAT2) expression levels were significantly decreased, accompanied by impaired glutamate clearance ability, in mut-SOD1 astrocytes; yin yang 1 (YY1), a transcriptional inhibitor for EAAT2, increased in nucleus of mut-SOD1 astrocytes. AEG-1 silence inhibited translocation of YY1 to nucleus, increased EAAT2 expression levels, and enhanced astrocytic ability of glutamate clearance, ultimately exerted the neuronal protection. Findings from this study implicate potential function of AEG-1 in mut-SOD1 related astrogliosis and the accompanied excitatory cytotoxic mechanism in ALS.
α4-GABAA receptors of hippocampal pyramidal neurons are associated with resilience against activity-based anorexia for adolescent female mice but not for males Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-04-22 Yi-Wen Chen, Hannah Actor-Engel, Chiye Aoki
Activity-based anorexia (ABA) is an animal model of anorexia nervosa, a mental illness with highest mortality and with onset that is most frequently during adolescence. We questioned whether vulnerability of adolescent mice to ABA differs between sexes and whether individual differences in resilience are causally linked to α4βδ-GABAAR expression. C57BL6/J WT and α4-KO adolescent male and female mice underwent ABA induction by combining wheel access with food restriction. ABA vulnerability was measured as the extent of food restriction-evoked hyperactivity on a running wheel and body weight losses. α4βδ-GABAAR levels at plasma membranes of pyramidal cells in dorsal hippocampus were assessed by electron microscopic immunocytochemistry. Temporal patterns and extent of weight loss during ABA induction were similar between sexes. Both sexes also exhibited individual differences in ABA vulnerability. Correlation analyses revealed that, for both sexes, body weight changes precede and thus are likely to drive suppression of wheel running. However, the suppression was during the food-anticipatory hours for males, while for females, suppression was delayed by a day and during food-access hours. Correspondingly, only females adaptively increased food intake. ABA induced up-regulation of α4βδ-GABAARs at plasma membranes of dorsal hippocampal pyramidal cells of females, and especially those females exhibiting resilience. Conversely, α4-KO females exhibited greater food restriction-evoked hyperactivity than WT females. In contrast, ABA males did not up-regulate α4βδ-GABAARs, did not exhibit genotype differences in vulnerability, and exhibited no correlation between plasmalemmal α4βδ-GABAARs and ABA resilience. Thus, food restriction-evoked hyperactivity is driven by anxiety but can be suppressed through upregulation of hippocampal α4βδ-GABAARs for females but not for males. This knowledge of sex-related differences in the underlying mechanisms of resilience to ABA indicates that drugs targeting α4βδ-GABAARs may be helpful for treating stress-induced anxiety and anorexia nervosa of females but not males.
Depletion of astrocytic transglutaminase 2 improves injury outcomes Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-06-30 Alina Monteagudo, Julianne Feola, Heather Natola, Changyi Ji, Christoph Pröschel, Gail V.W. Johnson
Astrocytes play an indispensable role in maintaining a healthy, functional neural network in the central nervous system (CNS). A primary function of CNS astrocytes is to support the survival and function of neurons. In response to injury, astrocytes take on a reactive phenotype, which alters their molecular functions. Reactive astrocytes have been reported to be both beneficial and harmful to the CNS recovery process subsequent to injury. Understanding the molecular processes and regulatory proteins that determine the extent to which an astrocyte hinders or supports neuronal survival is important within the context of CNS repair. One protein that plays a role in modulating cellular survival is transglutaminase 2 (TG2). Global deletion of TG2 results in beneficial outcomes subsequent to in vivo ischemic brain injury. Ex vivo studies have also implicated TG2 as a negative regulator of astrocyte viability subsequent to injury. In this study we show that knocking down TG2 in astrocytes significantly increases their ability to protect neurons from oxygen glucose deprivation (OGD)/reperfusion injury. To begin to understand how deletion of TG2 in astrocytes improves their ability to protect neurons from injury, we performed transcriptome analysis of wild type and TG2−/− astrocytes. TG2 deletion resulted in alterations in genes involved in extracellular matrix remodeling, cell adhesion and axon growth/guidance. In addition, the majority of genes that showed increases in the TG2−/− astrocytes had predicted cJun/AP-1 binding motifs in their promoters. Furthermore, phospho-cJun levels were robustly elevated in TG2−/− astrocytes, a finding which was consistent with the increase in expression of AP-1 responsive genes. These in vitro data were subsequently extended into an in vivo model to determine whether the absence of astrocytic TG2 improves outcomes after CNS injury. Our results show that, following a spinal cord injury, scar formation is significantly attenuated in mice with astrocyte-specific TG2 deletion compared to mice expressing normal TG2 levels. Taken together, these data indicate that TG2 plays a pivotal role in mediating reactive astrocyte properties following CNS injury. Further, the data suggest that limiting the AP-1 mediated pro-survival injury response may be a contributing factor to that the detrimental effects of astrocytic TG2.
Sex-dependent co-occurrence of hypoxia and β-amyloid plaques in hippocampus and entorhinal cortex is reversed by long-term treatment with ubiquinol and ascorbic acid in the 3 × Tg-AD mouse model of Alzheimer's disease Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-06-25 Javier Frontiñan-Rubio, Francisco J. Sancho-Bielsa, Juan R. Peinado, Frank M. LaFerla, Lydia Giménez-Llort, Mario Durán-Prado, Francisco J. Alcain
Structural and functional abnormalities in the cerebral microvasculature have been observed in Alzheimer's disease (AD) patients and animal models. One cause of hypoperfusion is the thickening of the cerebrovascular basement membrane (CVBM) due to increased collagen-IV deposition around capillaries. This study investigated whether these and other alterations in the cerebrovascular system associated with AD can be prevented by long-term dietary supplementation with the antioxidant ubiquinol (Ub) stabilized with Kaneka QH P30 powder containing ascorbic acid (ASC) in a mouse model of advanced AD (3 × Tg-AD mice, 12 months old). Animals were treated from prodromal stages of disease (3 months of age) with standard chow without or with Ub + ASC or ASC-containing vehicle and compared to wild-type (WT) mice. The number of β-amyloid (Aβ) plaques in the hippocampus and entorhinal cortex was higher in female than in male 3 × Tg-AD mice. Extensive regions of hypoxia were characterized by a higher plaque burden in females only. This was abolished by Ub + ASC and, to a lesser extent, by ASC treatment. Irrespective of Aβ burden, increased collagen-IV deposition in the CVBM was observed in both male and female 3 × Tg-AD mice relative to WT animals; this was also abrogated in Ub + ASC- and ASC-treated mice. The chronic inflammation in the hippocampus and oxidative stress in peripheral leukocytes of 3 × Tg-AD mice were likewise reversed by antioxidant treatment. These results provide strong evidence that long-term antioxidant treatment can mitigate plasma oxidative stress, amyloid burden, and hypoxia in the AD brain parenchyma.
AMPA receptor complex constituents: Control of receptor assembly, membrane trafficking and subcellular localization Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-05-26 Eric Jacobi, Jakob von Engelhardt
Fast excitatory transmission at synapses of the central nervous system is mainly mediated by AMPA receptors (AMPARs). Synaptic AMPAR number and function correlates with synaptic strength. AMPARs are thus key proteins of activity-dependent plasticity in neuronal communication. Up- or down-regulation of synaptic AMPAR number is a tightly controlled dynamic process that involves export of receptors from the endoplasmic reticulum (ER) and Golgi apparatus, exocytosis and endocytosis as well as lateral diffusion of the receptors in the cell membrane. The four AMPAR subunits are embedded into a dynamic network of more than 30 interacting proteins. Many of these proteins are known to modulate receptor gating, trafficking and subcellular localization. Here, we will review the influence that AMPAR interacting proteins exert on trafficking and subcellular localization of the receptors by controlling their assembly, ER/Golgi apparatus export, and synaptic anchoring.
Functional organization of postsynaptic glutamate receptors Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-05-16 Nicky Scheefhals, Harold D. MacGillavry
Glutamate receptors are the most abundant excitatory neurotransmitter receptors in the brain, responsible for mediating the vast majority of excitatory transmission in neuronal networks. The AMPA- and NMDA-type ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the fast synaptic responses, while metabotropic glutamate receptors (mGluRs) are coupled to downstream signaling cascades that act on much slower timescales. These functionally distinct receptor sub-types are co-expressed at individual synapses, allowing for the precise temporal modulation of postsynaptic excitability and plasticity. Intriguingly, these receptors are differentially distributed with respect to the presynaptic release site. While iGluRs are enriched in the core of the synapse directly opposing the release site, mGluRs reside preferentially at the border of the synapse. As such, to understand the differential contribution of these receptors to synaptic transmission, it is important to not only consider their signaling properties, but also the mechanisms that control the spatial segregation of these receptor types within synapses. In this review, we will focus on the mechanisms that control the organization of glutamate receptors at the postsynaptic membrane with respect to the release site, and discuss how this organization could regulate synapse physiology.
The functional architecture of axonal actin Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-05-12 Marie-Jeanne Papandréou, Christophe Leterrier
The cytoskeleton builds and supports the complex architecture of neurons. It orchestrates the specification, growth, and compartmentation of the axon: axon initial segment, axonal shaft, presynapses. The cytoskeleton must then maintain this intricate architecture for the whole life of its host, but also drive its adaptation to new network demands and changing physiological conditions. Microtubules are readily visible inside axon shafts by electron microscopy, whereas axonal actin study has long been focused on dynamic structures of the axon such as growth cones. Super-resolution microscopy and live-cell imaging have recently revealed new actin-based structures in mature axons: rings, hotspots and trails. This has caused renewed interest for axonal actin, with efforts underway to understand the precise organization and cellular functions of these assemblies. Actin is also present in presynapses, where its arrangement is still poorly defined, and its functions vigorously debated. Here we review the organization of axonal actin, focusing on recent advances and current questions in this rejuvenated field.
Autophagy and lysosomal pathways in nervous system disorders Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-05-03 Baris Bingol
Autophagy is an evolutionarily conserved pathway for delivering cytoplasmic cargo to lysosomes for degradation. In its classically studied form, autophagy is a stress response induced by starvation to recycle building blocks for essential cellular processes. In addition, autophagy maintains basal cellular homeostasis by degrading endogenous substrates such as cytoplasmic proteins, protein aggregates, damaged organelles, as well as exogenous substrates such as bacteria and viruses. Given their important role in homeostasis, autophagy and lysosomal machinery are genetically linked to multiple human disorders such as chronic inflammatory diseases, cardiomyopathies, cancer, and neurodegenerative diseases. Multiple targets within the autophagy and lysosomal pathways offer therapeutic opportunities to benefit patients with these disorders. Here, I will summarize the mechanisms of autophagy pathways, the evidence supporting a pathogenic role for disturbed autophagy and lysosomal degradation in nervous system disorders, and the therapeutic potential of autophagy modulators in the clinic.
Ankyrins: Roles in synaptic biology and pathology Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-05-03 Katharine R. Smith, Peter Penzes
Ankyrins are broadly expressed adaptors that organize diverse membrane proteins into specialized domains and link them to the sub-membranous cytoskeleton. In neurons, ankyrins are known to have essential roles in organizing the axon initial segment and nodes of Ranvier. However, recent studies have revealed novel functions for ankyrins at synapses, where they organize and stabilize neurotransmitter receptors, modulate dendritic spine morphology and control adhesion to the presynaptic site. Ankyrin genes have also been highly associated with a range of neurodevelopmental and psychiatric diseases, including bipolar disorder, schizophrenia and autism, which all demonstrate overlap in their genetics, mechanisms and phenotypes. This review discusses the novel synaptic functions of ankyrin proteins in neurons, and places these exciting findings in the context of ANK genes as key neuropsychiatric disorder risk-factors.
Dynamics, nanoscale organization, and function of synaptic adhesion molecules Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-04-17 Ingrid Chamma, Olivier Thoumine
Synaptic adhesion molecules not only provide a physical link between pre- and post-synaptic membranes, but also contribute to synaptic differentiation and plasticity by organizing functional elements, in particular neurotransmitter receptors. The wealth of existing adhesive protein families including many isoforms and splice variants, calls for systematic identification of the levels and exchange rates of each of those protein members at specific synapse types. Complementary to electron microscopy to identify individual synaptic contacts and biochemistry to reveal protein-protein interactions, recent super-resolution light microscopy methods combined with appropriate fluorescent labeling provide a way to measure the dynamics and sub-micron organization of selective molecular components, and their inter-relations at the synapse. In this review, we summarize current knowledge on the dynamics, nanoscale localization, and function of key synaptic adhesion complexes.
New approaches for solving old problems in neuronal protein trafficking Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-04-10 Ashley M. Bourke, Aaron B. Bowen, Matthew J. Kennedy
Fundamental cellular properties are determined by the repertoire and abundance of proteins displayed on the cell surface. As such, the trafficking mechanisms for establishing and maintaining the surface proteome must be tightly regulated for cells to respond appropriately to extracellular cues, yet plastic enough to adapt to ever-changing environments. Not only are the identity and abundance of surface proteins critical, but in many cases, their regulated spatial positioning within surface nanodomains can greatly impact their function. In the context of neuronal cell biology, surface levels and positioning of ion channels and neurotransmitter receptors play essential roles in establishing important properties, including cellular excitability and synaptic strength. Here we review our current understanding of the trafficking pathways that control the abundance and localization of proteins important for synaptic function and plasticity, as well as recent technological advances that are allowing the field to investigate protein trafficking with increasing spatiotemporal precision.
Trafficking mechanisms of synaptogenic cell adhesion molecules Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-04-06 Luís F. Ribeiro, Ben Verpoort, Joris de Wit
Nearly every aspect of neuronal function, from wiring to information processing, critically depends on the highly polarized architecture of neurons. Establishing and maintaining the distinct molecular composition of axonal and dendritic compartments requires precise control over the trafficking of the proteins that make up these cellular domains. Synaptic cell adhesion molecules (CAMs), membrane proteins with a critical role in the formation, differentiation and plasticity of synapses, require targeting to the correct pre- or postsynaptic compartment for proper functioning of neural circuits. However, the mechanisms that control the polarized trafficking, synaptic targeting, and synaptic abundance of CAMs are poorly understood. Here, we summarize current knowledge about the sequential trafficking events along the secretory pathway that control the polarized surface distribution of synaptic CAMs, and discuss how their synaptic targeting and abundance is additionally influenced by post-secretory determinants. The identification of trafficking-impairing mutations in CAMs associated with various neurodevelopmental disorders underscores the importance of correct protein trafficking for normal brain function.
Tetraspanins shape the synapse Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-04-06 Luca Murru, Edoardo Moretto, Giuseppe Martano, Maria Passafaro
Tetraspanins are a family of proteins largely expressed in mammals. These proteins share very similar structures and are involved in several biological processes spanning from the immune system to cancer growth regulation. Moreover, tetraspanins are scaffold proteins that are able to interact with each other and with a subset of proteins involved in the regulation of the central nervous system, including synapse formation, function and plasticity. In this review, we will focus on the analysis of the literature on tetraspanins, highlighting their involvement in synapse formation and function through direct or indirect modulation of synaptic proteins.
Metabotropic glutamate receptor trafficking Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-29 Young Ho Suh, Kai Chang, Katherine W. Roche
The metabotropic glutamate receptors (mGlu receptors) are G protein-coupled receptors that bind to the excitatory neurotransmitter glutamate and are important in the modulation of neuronal excitability, synaptic transmission, and plasticity in the central nervous system. Trafficking of mGlu receptors in and out of the synaptic plasma membrane is a fundamental mechanism modulating excitatory synaptic function through regulation of receptor abundance, desensitization, and signaling profiles. In this review, we cover the regulatory mechanisms determining surface expression and endocytosis of mGlu receptors, with particular focus on post-translational modifications and receptor-protein interactions. The literature we review broadens our insight into the precise events defining the expression of functional mGlu receptors at synapses, and will likely contribute to the successful development of novel therapeutic targets for a variety of developmental, neurological, and psychiatric disorders.
Mechanisms of neurotrophin trafficking via Trk receptors Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-27 Emily Scott-Solomon, Rejji Kuruvilla
In neurons, long-distance communication between axon terminals and cell bodies is a critical determinant in establishing and maintaining neural circuits. Neurotrophins are soluble factors secreted by post-synaptic target tissues that retrogradely control axon and dendrite growth, survival, and synaptogenesis of innervating neurons. Neurotrophins bind Trk receptor tyrosine kinases in axon terminals to promote endocytosis of ligand-bound phosphorylated receptors into signaling endosomes. Trk-harboring endosomes function locally in axons to acutely promote growth events, and can also be retrogradely transported long-distances to remote cell bodies and dendrites to stimulate cytoplasmic and transcriptional signaling necessary for neuron survival, morphogenesis, and maturation. Neuronal responsiveness to target-derived neurotrophins also requires the precise axonal targeting of newly synthesized Trk receptors. Recent studies suggest that anterograde delivery of Trk receptors is regulated by retrograde neurotrophin signaling. In this review, we summarize current knowledge on the functions and mechanisms of retrograde trafficking of Trk signaling endosomes, and highlight recent discoveries on the forward trafficking of nascent receptors.
Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-24 Murat Kilinc, Thomas Creson, Camilo Rojas, Massimiliano Aceti, Jacob Ellegood, Thomas Vaissiere, Jason P. Lerch, Gavin Rumbaugh
SYNGAP1 loss-of-function variants are causally associated with intellectual disability, severe epilepsy, autism spectrum disorder and schizophrenia. While there are hundreds of genetic risk factors for neurodevelopmental disorders (NDDs), this gene is somewhat unique because of the frequency and penetrance of loss-of-function variants found in patients combined with the range of brain disorders associated with SYNGAP1 pathogenicity. These clinical findings indicate that SYNGAP1 regulates fundamental neurodevelopmental processes that are necessary for brain development. Here, we describe four phenotypic domains that are controlled by Syngap1 expression across vertebrate species. Two domains, the maturation of cognitive functions and maintenance of excitatory-inhibitory balance, are defined exclusively through a review of the current literature. Two additional domains are defined by integrating the current literature with new data indicating that SYNGAP1/Syngap1 regulates innate survival behaviors and brain structure. These four phenotypic domains are commonly disrupted in NDDs, suggesting that a deeper understanding of developmental Syngap1 functions will be generalizable to other NDDs of known or unknown etiology. Therefore, we discuss the known molecular and cellular functions of Syngap1 and consider how these functions may contribute to the emergence of disease-relevant phenotypes. Finally, we identify major unexplored areas of Syngap1 neurobiology and discuss how a deeper understanding of this gene may uncover general principles of NDD pathobiology.
Microtubules and axon regeneration in C. elegans Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-16 Lizhen Chen
Axon regeneration is a fundamental and conserved process that allows the nervous system to repair circuits after trauma. Due to its conserved genome, transparent body, and relatively simple neuroanatomy, C. elegans has become a powerful model organism for studying the cellular and molecular mechanisms underlying axon regeneration. Various studies from different model organisms have found microtubule dynamics to be pivotal to axon regrowth. In this review, we will discuss the latest findings on how microtubule dynamics are regulated during axon regeneration in C. elegans. Understanding the mechanisms of axon regeneration will aid in the development of more effective therapeutic strategies for treatments of diseases involving disconnection of axons, such as spinal cord injury and stroke.
Regulation of AMPA receptor trafficking and exit from the endoplasmic reticulum Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-12 Joseph E. Pick, Edward B. Ziff
A fundamental property of the brain is its ability to modify its function in response to its own activity. This ability for self-modification depends to a large extent on synaptic plasticity. It is now appreciated that for excitatory synapses, a significant part of synaptic plasticity depends upon changes in the post synaptic response to glutamate released from nerve terminals. Modification of the post synaptic response depends, in turn, on changes in the abundances of AMPA receptors in the post synaptic membrane. In this review, we consider mechanisms of trafficking of AMPA receptors to and from synapses that take place in the early trafficking stages, starting in the endoplasmic reticulum (ER) and continuing into the secretory pathway. We consider mechanisms of AMPA receptor assembly in the ER, highlighting the role of protein synthesis and the selective properties of specific AMPA receptor subunits, as well as regulation of ER exit, including the roles of chaperones and accessory proteins and the incorporation of AMPA receptors into COPII vesicles. We consider these processes in the context of the mechanism of mGluR LTD and discuss a compelling role for the dendritic ER membrane that is found proximal to synapses. The review illustrates the important, yet little studied, contribution of the early stages of AMPA receptor trafficking to synaptic plasticity.
Cystatin C promotes tau protein phosphorylation and causes microtubule instability by inhibiting intracellular turnover of GSK3β in neurons Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-22 Jinhai Duan, Kristen A. Marcellus, Xike Qin, Yunling Wang, Hemant K. Paudel
In Alzheimer's disease (AD) tau protein hyperphosphorylation causes neurofibrillary tangle formation, microtubule instability and neurodegeneration. Determining the mechanism of tau hyperphosphorylation will provide a better understanding of AD pathology. Cystatin C (CysC) is a risk factor for late-onset AD and its level is upregulated in the brains of AD patients. The role of CysC is AD pathogenesis is not known. In this study, we found that CysC level is upregulated in 3xTg-AD mouse brain. We demonstrate that CysC does not affect cellular Aβ production. However, when overexpressed in neuron (NGF-differentiated PC12 cells), CysC inhibits turnover of GSK3β, promotes GSK3β-catalyzed tau phosphorylation at Ser396/404 and causes microtubule instability. Our data provide a novel insight into the role of CysC in AD pathogenesis.
The transmembrane collagen COL-99 guides longitudinally extending axons in C. elegans Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-15 Jesse Taylor, Thomas Unsoeld, Harald Hutter
We have identified the transmembrane collagen, COL-99, in a genetic screen for novel genes involved in axon guidance in the nematode C. elegans. COL-99 is similar to transmembrane collagens type XIII, XXIII and XXV in vertebrates. col-99 mutants exhibit guidance defects in axons extending along the major longitudinal axon tracts, most prominently the left ventral nerve cord (VNC). COL-99 is expressed in the hypodermis during the time of axon outgrowth. We provide evidence that a furin cleavage site in COL-99 is essential for function, suggesting that COL-99 is released from the cells producing it. Vertebrate homologs of COL-99 have been shown to be expressed in mammalian nervous systems and linked to various neurological disease but have not been associated with guidance of extending neurons. col-99 acts genetically with the discoidin domain receptors ddr-1 and ddr-2, which are expressed by neurons affected in col-99 mutants. Discoidin domain receptors are activated by collagens in vertebrates. DDR-1 and DDR-2 may function as receptors for COL-99. Our results establish a novel role for a transmembrane collagen in axonal guidance and asymmetry establishment of the VNC.
d-Serine administration affects nitric oxide synthase 1 adaptor protein and DISC1 expression in sex-specific manner Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-27 Kirsten C. Svane, Ericka-Kate Asis, Anton Omelchenko, Ansley J. Kunnath, Linda M. Brzustowicz, Steven M. Silverstein, Bonnie L. Firestein
Deletion of the endogenous TrkB.T1 receptor isoform restores the number of hippocampal CA1 parvalbumin-positive neurons and rescues long-term potentiation in pre-symptomatic mSOD1(G93A) ALS mice Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-24 Eros Quarta, Gianluca Fulgenzi, Riccardo Bravi, Erez James Cohen, Sudhirkumar Yanpallewar, Lino Tessarollo, Diego Minciacchi
Amyotrophic lateral sclerosis (ALS) causes rapidly progressive paralysis and death within 5 years from diagnosis due to degeneration of the motor circuits. However, a significant population of ALS patients also shows cognitive impairments and progressive hippocampal pathology. Likewise, the mutant SOD1(G93A) mouse model of ALS (mSOD1), in addition to loss of spinal motor neurons, displays altered spatial behavior and hippocampal abnormalities including loss of parvalbumin-positive interneurons (PVi) and enhanced long-term potentiation (LTP). However, the cellular and molecular mechanisms underlying these morpho-functional features are not well understood. Since removal of TrkB.T1, a receptor isoform of the brain-derived neurotrophic factor, can partially rescue the phenotype of the mSOD1 mice, here we tested whether removal of TrkB.T1 can normalize the number of PVi and the LTP in this model. Stereological analysis of hippocampal PVi in control, TrkB.T1−/−, mSOD1, and mSOD1 mice deficient for TrkB.T1 (mSOD1/T1−/−) showed that deletion of TrkB.T1 restored the number of PVi to physiological level in the mSOD1 hippocampus. The rescue of PVi neuron number is paralleled by a normalization of high-frequency stimulation-induced LTP in the pre-symptomatic mSOD1/T1−/− mice. Our experiments identified TrkB.T1 as a cellular player involved in the homeostasis of parvalbumin expressing interneurons and, in the context of murine ALS, show that TrkB.T1 is involved in the mechanism underlying structural and functional hippocampal degeneration. These findings have potential implications for hippocampal degeneration and cognitive impairments reported in ALS patients at early stages of the disease.
Anti-GM1 ganglioside antibodies modulate membrane-associated sphingomyelin metabolism by altering neutral sphingomyelinase activity Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-03-27 Akihiro Ueda, Sayuri Shima, Kenitiroh Murate, Kouichi Kikuchi, Ryunosuke Nagao, Toshiki Maeda, Eri Muto, Yoshiki Niimi, Yasuaki Mizutani, Tatsuro Mutoh
Previous studies have shown that patients with Guillain-Barré syndrome express autoantibodies against ganglioside GM1 (GM1), although its pathogenic significance for the development of the disease remains to be elucidated. nSMase2 is the best characterized neutral sphingomyelinase (nSMase) found in neuronal cells. Activation of this enzyme leads to ceramide production, which is a known second messenger of the cell-death program in neuronal cells. We have explored the effects of anti-GM1 antibodies on sphingomyelin metabolism of PC12 cells stably transfected with human trk cDNA (PCtrk cells) by determining their effects on nSMase2 activity. The data we present here strongly suggest that anti-GM1 caused a significant change in sphingomyelin content of the membrane fraction in PCtrk cells. Both nSMase2 activity and the level of nSMase2 protein were significantly decreased by anti-GM1 treatment of PCtrk cells, while acidic SMase activities remained unchanged. Our results indicate, for the first time, that anti-GM1 may produce profound impacts on lipid metabolism in neuronal cell membranes.
Trans ε-viniferin is an amyloid-β disaggregating and anti-inflammatory drug in a mouse primary cellular model of Alzheimer's disease Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2017-12-07 Elodie Vion, Guylène Page, Eric Bourdeaud, Marc Paccalin, Jérôme Guillard, Agnès Rioux Bilan
Alzheimer's disease (AD) is marked by several cellular and molecular damage. Therefore, the therapeutic interest of multi-target molecules is increasingly justified. Polyphenols presenting multiple pharmacological effects would be more efficient. In this study, beneficial effects of trans ε-viniferin, a natural polyphenol were thus evaluated. This study reported that this stilbenoid (1) induced the disaggregation of amyloid β (Aβ) peptide and (2) rescued inflammation in murine primary neuronal cultures. These both effects are higher than those of resveratrol, and so, trans ε-viniferin could be a good therapeutic multi-target candidate.
Ca2+ mediates axotomy-induced necrosis and apoptosis of satellite glial cells remote from the transection site in the isolated crayfish mechanoreceptor Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2017-12-08 Andrey Khaitin, Mikhail Rudkovskii, Anatoly Uzdensky
Impaired neurogenesis and associated gliosis in mouse brain with PEX13 deficiency Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2017-12-02 Rani Sadia Rahim, James A. St John, Denis I. Crane, Adrian C.B. Meedeniya
Zellweger syndrome (ZS), a neonatal lethal disorder arising from defective peroxisome biogenesis, features profound neuroanatomical abnormalities and brain dysfunction. Here we used mice with brain-restricted inactivation of the peroxisome biogenesis gene PEX13 to model the pathophysiological features of ZS, and determine the impact of peroxisome dysfunction on neurogenesis and cell maturation in ZS. In the embryonic and postnatal PEX13 mutant brain, we demonstrate key regions with altered brain anatomy, including enlarged lateral ventricles and aberrant cortical, hippocampal and hypothalamic organization. To characterize the underlying mechanisms, we show a significant reduction in proliferation, migration, differentiation, and maturation of neural progenitors in embryonic E12.5 through to P3 animals. An increasing reactive gliosis in the PEX13 mutant brain started at E14.5 in association with the pathology. Together with impaired neurogenesis and associated gliosis, our data demonstrate increased cell death contributing to the hallmark brain anatomy of ZS. We provide unique data where impaired neurogenesis and migration are shown as critical events underlying the neuropathology and altered brain function of mice with peroxisome deficiency.
Munc18-1 haploinsufficiency impairs learning and memory by reduced synaptic vesicular release in a model of Ohtahara syndrome Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2017-12-05 Albert Orock, Sreemathi Logan, Ferenc Deak
Ohtahara syndrome, also known as type 4 of Early Infantile Epileptic Encephalopathy with suppression bursts (EIEE-4) is currently an untreatable disorder that presents with seizures and impaired cognition. EIEE-4 patients have mutations most frequently in the STXBP1 gene encoding a Sec protein, munc18-1. The exact molecular mechanism of how these munc18-1 mutations cause impaired cognition, remains elusive. The leading haploinsufficiency hypothesis posits that mutations in munc18-1 render the protein unstable leading to its degradation. Expression driven by the healthy allele is not sufficient to maintain the physiological function resulting in haploinsufficiency. The aim of this study has been to understand how munc18-1 haploinsufficiency causes cognitive impairment seen in EIEE-4. Here we present results from behavioral to cellular effects from a mouse model of munc18-1 haploinsufficiency. Munc18-1 heterozygous knock-out mice showed impaired spatial learning and memory in behavior tests as well as reduced synaptic plasticity in hippocampal CA1 long-term potentiation. Cultured munc18-1 heterozygous hippocampal neurons had significantly slower rate of synaptic vesicle release and decreased readily releasable vesicle pool compared to wild-type control neurons in fluorescent FM dye assays. These results demonstrate that reduced munc18-1 levels are sufficient to impair learning and memory by reducing neurotransmitter release. Therefore, our study implicates munc18-1 haploinsufficiency as a primary cause of cognitive impairment seen in EIEE-4 patients.
Aberrant subcellular localization of SQSTM1/p62 contributes to increased vulnerability to proteotoxic stress recovery in Huntington's disease Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2017-12-12 Ningjing Huang, Christine Erie, Michael L. Lu, Jianning Wei
Evidence for astrocyte purinergic signaling in cortical sensory adaptation and serotonin-mediated neuromodulation Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2017-12-22 Elizabeth F. Quon, Caitlin A. Wotton, Lane K. Bekar
In the somatosensory cortex, inhibitory networks are involved in low frequency sensory input adaptation/habituation that can be observed as a paired-pulse depression when using a dual stimulus electrophysiological paradigm. Given that astrocytes have been shown to regulate inhibitory interneuron activity, we hypothesized that astrocytes are involved in cortical sensory adaptation/habituation and constitute effectors of the 5HT-mediated increase in frequency transmission. Using extracellular recordings of evoked excitatory postsynaptic potentials (eEPSPs) in layer II/III of somatosensory cortex, we used various pharmacological approaches to assess the recruitment of astrocyte signaling in paired-pulse depression and serotonin-mediated increase in the paired-pulse ratio (pulse 2/pulse 1). In the absence of neuromodulators or pharmacological agents, the first eEPSP is much larger in amplitude than the second due to the recruitment of long-lasting evoked GABAA-dependent inhibitory activity from the first stimulus. Disruption of glycolysis or mGluR5 signaling resulted in a very similar loss of paired-pulse depression in field recordings. Interestingly, paired-pulse depression was similarly sensitive to disruption by ATP P2Y and adenosine A2A receptor antagonists. In addition, we show that pharmacological disruption of paired-pulse depression by mGluR5, P2Y, and glycolysis inhibition precluded serotonin effects on frequency transmission (typically increased the paired-pulse ratio). These data highlight the possibility for astrocyte involvement in cortical inhibitory activity seen in this simple cortical network and that serotonin may act on astrocytes to exert some aspects of its modulatory influence.
Proteasome phosphorylation regulates cocaine-induced sensitization Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2017-12-05 Frankie R. Gonzales, Kristin K. Howell, Lara E. Dozier, Stephan G. Anagnostaras, Gentry N. Patrick
Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson's disease Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-02-03 Abeje Ambaw, Lingxing Zheng, Mitali A. Tambe, Katherine E. Strathearn, Glen Acosta, Scott A. Hubers, Fang Liu, Seth A. Herr, Jonathan Tang, Alan Truong, Elwood Walls, Amber Pond, Jean-Christophe Rochet, Riyi Shi
Growing evidence suggests that oxidative stress plays a critical role in neuronal destruction characteristic of Parkinson's disease (PD). However, the molecular mechanisms of oxidative stress-mediated dopaminergic cell death are far from clear. In the current investigation, we tested the hypothesis that acrolein, an oxidative stress and lipid peroxidation (LPO) product, is a key factor in the pathogenesis of PD. Using a combination of in vitro, in vivo, and cell free models, coupled with anatomical, functional, and behavioral examination, we found that acrolein was elevated in 6-OHDA-injected rats, and behavioral deficits associated with 6-OHDA could be mitigated by the application of the acrolein scavenger hydralazine, and mimicked by injection of acrolein in healthy rats. Furthermore, hydralazine alleviated neuronal cell death elicited by 6-OHDA and another PD-related toxin, rotenone, in vitro. We also show that acrolein can promote the aggregation of alpha-synuclein, suggesting that alpha-synuclein self-assembly, a key pathological phenomenon in human PD, could play a role in neurotoxic effects of acrolein in PD models. These studies suggest that acrolein is involved in the pathogenesis of PD, and the administration of anti-acrolein scavengers such as hydralazine could represent a novel strategy to alleviate tissue damage and motor deficits associated with this disease.
A small peptide derived from BMP-9 can increase the effect of bFGF and NGF on SH-SY5Y cells differentiation Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-01-16 Marc-Antoine Lauzon, Nathalie Faucheux
The current aging of the world population will increase the number of people suffering from brain degenerative diseases such as Alzheimer's disease (AD). There are evidence showing that the use of growth factors such as BMP-9 could restored cognitive function as it acts on many AD hallmarks at the same time. However, BMP-9 is a big protein expensive to produce that can hardly access the central nervous system. We have therefore developed a small peptide, SpBMP-9, derived from the knuckle epitope of BMP-9 and showed its therapeutic potential in a previous study. Since it is known that the native protein, BMP-9, can act in synergy with other growth factors in the context of AD, here we study the potential synergistic effect of various combinations of SpBMP-9 with bFGF, EGF, IGF-2 or NGF on the cholinergic differentiation of human neuroblastoma cells SH-SY5Y. We found that, in opposition to IGF-2 or EGF, the combination of SpBMP-9 with bFGF or NGF can stimulate to a greater extent the neurite outgrowth and neuronal differentiation toward the cholinergic phenotype as shown by expression and localization of the neuronal markers NSE and VAchT and the staining of intracellular calcium. Those results strongly suggest that SpBMP-9 plus NGF or bFGF are promising therapeutic combinations against AD that required further attention.
Aging exacerbates cognitive and anxiety alterations induced by an intracerebroventricular injection of amyloid-β1–42 peptide in mice Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-02-03 Leandro Cattelan Souza, Cristiano R. Jesse, Lucian Del Fabbro, Marcelo Gomes de Gomes, Nathalie Savedra Gomes, Carlos Borges Filho, André Tiago Rossito Goes, Ethel Antunes Wilhelm, Cristiane Luchese, Silvane Souza Roman, Silvana Peterini Boeira
An increasing body of evidence indicates that the activation of indoleamine-2,3-dyoxigenase (IDO), a first and rate-limiting enzyme in the kynurenine (KYN) pathway, is involved in Aβ1–42-neurotoxicity and AD pathogenesis. We have reported for the first time that brain IDO activation is related to Aβ1–42 exposure in young mice. Because aging is characterized by a brain dyshomeostasis and because it remains the most dominant risk factor for AD, the purpose of this study was to determine whether aging is associated with a higher sensitivity to behavioural and neurochemical alterations elicited by an intracerebroventricular (i.c.v.) injection of Aβ1–42 (400 pmol/mice), and whether KYN pathway is involved in these effects. We confirmed that aged mice displayed higher cognitive deficit in the object recognition test and higher anxiety-like behaviour in the elevated plus-maze and open field tests after the Aβ1–42 administration. Aged mice also responded to Aβ1–42 with a higher deficiency of brain-derived neurotrophic factor, glutathione levels and total radical-trapping antioxidant capacity, a higher IDO activity, and a higher KYN and KYN/tryptophan ratio in the prefrontal cortex and hippocampus. These effects of Aβ1–42 were associated with a higher proinflammatory status, as measured by higher levels of interleukin-6, lower levels of interleukin-10 and higher expression of glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (Iba1) in the brain of aged mice. These results represent primary evidence suggesting that age-associated inflammatory signature and down-regulation of neuroprotectants in the brain render aged mice more vulnerable to Aβ1–42-induced memory loss, anxiety symptoms and KYN pathway dysregulation.
Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-02-03 Jimena Hebe Martinez, Agustina Alaimo, Roxana Mayra Gorojod, Soledad Porte Alcon, Federico Fuentes, Federico Coluccio Leskow, Mónica Lidia Kotler
Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of α-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown. In the present work we investigated the effect of α-synuclein on mitochondrial dynamics and autophagy/mitophagy in SH-SY5Y cells, an in vitro model of Parkinson disease. We demonstrated that overexpression of wild type α-synuclein causes moderated toxicity, ROS generation and mitochondrial dysfunction. In addition, α-synuclein induces the mitochondrial fragmentation on a Drp-1-dependent fashion. Overexpression of the fusion protein Opa-1 prevented both mitochondrial fragmentation and cytotoxicity. On the other hand, cells expressing α-synuclein showed activated autophagy and particularly mitophagy. Employing a genetic strategy we demonstrated that autophagy is triggered in order to protect cells from α-synuclein-induced cell death. Our results clarify the role of Opa-1 and Drp-1 in mitochondrial dynamics and cell survival, a controversial α-synuclein research issue. The findings presented point to the relevance of mitochondrial homeostasis and autophagy in the pathogenesis of PD. Better understanding of the molecular interaction between these processes could give rise to novel therapeutic methods for PD prevention and amelioration.
Perturbations in the p53/miR-34a/SIRT1 pathway in the R6/2 Huntington's disease model Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2017-12-28 Regina Hertfelder Reynolds, Maria Hvidberg Petersen, Cecilie Wennemoes Willert, Marie Heinrich, Nynne Nymann, Morten Dall, Jonas T. Treebak, Maria Björkqvist, Asli Silahtaroglu, Lis Hasholt, Anne Nørremølle
Reproductive role of miRNA in the hypothalamic-pituitary axis Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-02-03 Chunyu Cao, Yifei Ding, Xiangjun Kong, Guangde Feng, Wei Xiang, Long Chen, Fang Yang, Ke Zhang, Mingxing Chu, Pingqing Wang, Baoyun Zhang
The hypothalamic-pituitary-gonadal (HPG) axis plays a critical role in regulating reproductive function. Gonadotropin-releasing hormone (GnRH), which is secreted by the hypothalamus, acts on pituitary gonadotrophs to stimulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and secretion, ultimately affecting the animal's fertility. MicroRNAs are small, non-coding RNAs that are widely expressed throughout the brain and can fine-tune gene expression post-transcriptionally. Recently, growing evidence has unveiled the central position of miRNAs within a key regulatory process involving GnRH secretion and subsequent activation in the pituitary. Although transcriptional regulation of reproduction has been well studied, the post-transcriptional processes are less well understood. In this review, we elaborate comprehensively on the critical role of miRNAs in the reproductive process, including both temporal and spatial aspects. A better understanding of how miRNAs impact the neuroendocrine system may improve our knowledge of reproduction and provide novel targets for therapeutic development.
G-protein coupled receptors Mc4r and Drd1a can serve as surrogate odorant receptors in mouse olfactory sensory neurons Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-01-31 Markella Katidou, Xavier Grosmaitre, Jiangwei Lin, Peter Mombaerts
In the mouse, most mature olfactory sensory neurons (OSNs) express one allele of one gene from the repertoire of ~1100 odorant receptor (OR) genes, which encode G-protein coupled receptors (GPCRs). Axons of OSNs that express a given OR coalesce into homogeneous glomeruli, which reside at conserved positions in the olfactory bulb. ORs are intimately involved in ensuring the expression of one OR per OSN and the coalescence of OSN axons into glomeruli. But the mechanisms whereby ORs accomplish these diverse functions remain poorly understood. An experimental approach that has been informative is to substitute an OR genetically with another GPCR that is normally not expressed in OSNs, in order to determine in which aspects this GPCR can serve as surrogate OR in mouse OSNs. Thus far only the β2-adrenergic receptor (β2AR, Ardb2) has been shown to be able to serve as surrogate OR in OSNs; the β2AR could substitute for the M71 OR in all aspects examined. Can other non-olfactory GPCRs function equally well as surrogate ORs in OSNs? Here, we have generated and characterized two novel gene-targeted mouse strains in which the mouse melanocortin 4 receptor (Mc4r) or the mouse dopamine receptor D1 (Drd1a) is coexpressed with tauGFP in OSNs that express the OR locus M71. These alleles and strains are abbreviated as Mc4r → M71-GFP and Drd1a → M71-GFP. We detected strong Mc4r or Drd1a immunoreactivity in axons and dendritic knobs and cilia of OSNs that express Mc4r or Drd1a from the M71 locus. These OSNs responded physiologically to cognate agonists for Mc4r (Ro27-3225) or Drd1a (SKF81297), and not to the M71 ligand acetophenone. Axons of OSNs expressing Mc4r → M71-GFP coalesced into glomeruli. Axons of OSNs expressing Drd1a → M71-GFP converged onto restricted areas of the olfactory bulb but did not coalesce into glomeruli. Thus, OR functions in OSNs can be substituted by Mc4r or Drd1a, but not as well as by β2AR. We attribute the weak performance of Drd1a as surrogate OR to poor OSN maturation.
Arginase-1 expressing microglia in close proximity to motor neurons were increased early in disease progression in canine degenerative myelopathy, a model of amyotrophic lateral sclerosis Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-02-20 Christine M. Toedebusch, John C. Snyder, Maria R. Jones, Virginia B. Garcia, Gayle C. Johnson, Eric L. Villalón, Joan R. Coates, Michael L. Garcia
Toxicity within superoxide dismutase-1 (SOD1)-associated familial amyotrophic lateral sclerosis (ALS) is non-cell autonomous with direct contribution from microglia. Microglia exhibit variable expression of neuroprotective and neurotoxic molecules throughout disease progression. The mechanisms regulating microglial phenotype within ALS are not well understood. This work presents a first study to examine the specific microglial phenotypic response in close association to motor neurons in a naturally occurring disease model of ALS, canine degenerative myelopathy (DM). Microglia closely associated with motor neurons were increased in all stages of DM progression, although only DM Late reached statistical significance. Furthermore, the number of arginase-1 expressing microglia per motor neuron were significantly increased in early stages of DM, whereas the number of inducible nitric oxide synthase (iNOS)-expressing microglia per motor neuron was indistinguishable from aged controls at all stages of disease. Fractalkine, a chemotactic molecule for microglia, was expressed in motor neurons, and the fractalkine receptor was specifically localized to microglia. However, we found no correlation between microglial response and lumbar spinal cord fractalkine levels. Taken together, these data suggest that arginase-1-expressing microglia are recruited to the motor neuron early in DM disease through a fractalkine-independent mechanism.
Exosome-associated tau exacerbates brain functional impairments induced by traumatic brain injury in mice Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-02-03 Bo Wang, Shuangshuang Han
Traumatic brain injury (TBI) has been associated with an increased risk for neurodegenerative diseases, and Tau spread and accumulation might be one of the mechanisms underlying this process. Exosomes were speculated to be a vehicle for spreading Tau in neurodegenerative diseases. The present study sought to investigate the effect of exosome associated Tau after TBI. C57BL/6J mice were subjected to controlled cortical impact injury and the levels of total and phosphorylated Tau in exosomes were measured. Then we isolated exosomes from wildtype and Tau-knockout mice after TBI. These exosomes were either added to primary cultured neurons to evaluate the toxicity, or injected into brains of mice subjected to TBI to evaluate the effect on brain functions. The levels of total and phosphorylated Tau in exosomes after TBI were significantly elevated. TBI derived exosomes displayed toxicity in primary neuron cultures, exacerbated TBI induced LTP (long-term potentiation) impairment and exacerbated motor and cognitive impairments after TBI. The exosome-associated Tau pathology was one of the mechanisms underlying the long-term neurodegenerative effect after TBI.
Neuroglobin overexpression plays a pivotal role in neuroprotection through mitochondrial raft-like microdomains in neuroblastoma SK-N-BE2 cells Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-01-31 Tina Garofalo, Alberto Ferri, Maurizio Sorice, Pardis Azmoon, Maria Grasso, Vincenzo Mattei, Antonella Capozzi, Valeria Manganelli, Roberta Misasi
Since stressing conditions induce a relocalization of endogenous human neuroglobin (NGB) to mitochondria, this research is aimed to evaluate the protective role of NGB overexpression against neurotoxic stimuli, through mitochondrial lipid raft-associated complexes. To this purpose, we built a neuronal model of oxidative stress by the use of human dopaminergic neuroblastoma cells, SK-N-BE2, stably overexpressing NGB by transfection and treated with 1-methyl-4-phenylpyridinium ion (MPP+). We preliminary observed the redistribution of NGB to mitochondria following MPP+ treatment. The analysis of mitochondrial raft-like microdomains revealed that, following MPP+ treatment, NGB translocated to raft fractions (Triton X-100-insoluble), where it interacts with ganglioside GD3. Interestingly, the administration of agents capable of perturbating microdomain before MPP+ treatment, significantly affected viability in SK-N-BE2-NGB cells. The overexpression of NGB was able to abrogate the mitochondrial injuries on complex IV activity or mitochondrial morphology induced by MPP+ administration. The protective action of NGB on mitochondria only takes place if the mitochondrial lipid(s) rafts-like microdomains are intact, indeed NGB fails to protect complex IV activity when purified mitochondria were treated with the lipid rafts disruptor methyl-β-cyclodextrin. Thus, our unique in vitro model of stably transfected cells overexpressing endogenous NGB allowed us to suggest that the role in neuroprotection played by NGB is reliable only through interaction with mitochondrial lipid raft-associated complexes.
Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-02-03 X. Du, K. Serena, W. Hwang, A.M. Grech, Y.W.C. Wu, A. Schroeder, R.A. Hill
Brain-derived neurotrophic factor (BDNF) is known to play a critical role early in the development of cortical GABAergic interneurons. Recently our laboratory and others have shown protracted development of specific subpopulations of GABAergic interneurons extending into adolescence. BDNF expression also changes significantly across adolescent development. However the role of BDNF in regulating GABAergic changes across adolescence remains unclear. Here, we performed a week-by-week analysis of the protein expression and cell density of three major GABAergic interneurons, parvalbumin (PV), somatostatin (SST) and calretinin (Cal) in the medial prefrontal cortex from prepubescence (week 3) to adulthood (week 12). In order to assess how BDNF and sex might influence the adolescent trajectory of GABAergic interneurons we compared WT as well as BDNF heterozygous (+/−) male and female mice. In both males and females PV expression increases during adolescent development in the mPFC. Compared to wild-types, PV expression was reduced in male but not female BDNF+/− mice throughout adolescent development. This reduction in protein expression corresponded with reduced cell density, specifically within the infralimbic prefrontal cortex. SST expression increased in early adolescent WT females and this upregulation was delayed in BDNF+/−. SST cell density also increased in early adolescent mPFC of WT female mice, with BDNF+/− again showing a reduced pattern of expression. Cal protein expression was also sex-dependently altered across adolescence with WT males showing a steady decline but that of BDNF+/− remaining unaltered. Reduced cell density in on the other hand was observed particularly in male BDNF+/− mice. In females, Cal protein expression and cell density remained largely stable. Our results show that PV, SST and calretinin interneurons are indeed still developing into early adolescence in the mPFC and that BDNF plays a critical, sex-specific role in mediating expression and cell density.
Schwann cell lamellipodia regulate cell-cell interactions and phagocytosis Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-01-11 Johana Tello Velasquez, James A. St John, Lynn Nazareth, Jenny A.K. Ekberg
Beta estradiol and norepinephrine treatment of differentiated SH-SY5Y cells enhances tau phosphorylation at (Ser396) and (Ser262) via AMPK but not mTOR signaling pathway Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-02-07 Shohreh Majd, Zohreh Majd, Simon Koblar, John Power
Hyperphosphorylation of tau is one of the main hallmarks for Alzheimer's disease (AD) and many other tauopathies. Norepinephrine (NE), a stress-related hormone and 17-β-estradiol (E2) thought to influence tau phosphorylation (p-tau) and AD pathology. The controversy around the impact of NE and E2 requires further clarification. Moreover, the combination effect of physiological and psychological stress and estrogen alteration during menopause, which affect p-tau, has not been addressed. Exposure to E2 is believed to reduce NE release, however, the link between these two hormones and AD at cellular level was also remained unknown. Here, we examined whether NE and E2 treatment of differentiated SH-SY5Y cells affected tau phosphorylation. The involvement of adenosine monophosphate kinase protein kinase (AMPK) and target of Rapamycin (mTOR) as the possible mechanisms, underlying this effect was also investigated. Subsequent to SH-SY5Y differentiation to mature neurons, we treated the cells with NE, E2 and NE plus E2 in presence and absence of Compound C and Rapamycin. Cell viability was not affected by our treatment while our Western blot and immunofluorescent findings showed that exposure to NE and E2 separately, and in combination enhanced p-tau (Ser396) and (Ser262)/tau but not (Ser202/Thr205)/tau. Blocking AMPK by Compound C reduced p-tau (Ser396) and (Ser262), while GSK-3β and PP2A activities were remained unchanged. We also found that blocking mTOR by Rapamycin did not change increased p-tau (Ser396) and (Ser262) due to NE + E2 treatment. Collectively, our results suggested that tau hyperphosphorylation due to exposure to NE/E2 was mediated by AMPK, the main energy regulator of cells during stress with no significant involvement of mTOR, GSK-3β and PP2A.
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