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  • Cyclo(His-Pro) inhibits NLRP3 inflammasome cascade in ALS microglial cells
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-11-13
    Silvia Grottelli, Letizia Mezzasoma, Paolo Scarpelli, Ivana Cacciatore, Barbara Cellini, Ilaria Bellezza

    Neuroinflammation, i.e. self-propelling progressive cycle of microglial activation and neuron damage, as well as improper protein folding, are recognized as major culprits of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Mutations in several proteins have been linked to ALS pathogenesis, including the G93A mutation in the superoxide dismutase 1 (SOD1) enzyme. SOD1(G93A) mutant is prone to aggregate thus inducing both oxidative stress and neuroinflammation. In this study we used hSOD1(G93A) microglial cells to investigate the effects of the antioxidant and anti-inflammatory cyclic dipeptide (His-Pro) on LPS-induced inflammasome activation. We found that cyclo(His-Pro) inhibits NLRP3 inflammasome activation by reducing protein nitration via reduction in NO and ROS levels, indicative of lower peroxynitrite generation by LPS. Low levels in peroxynitrite are related to NF-κB inhibition responsible for iNOS down-regulation and NO dampening. On the other hand, cyclo(His-Pro)-mediated ROS attenuation, not linked to Nrf2 activation in this cellular model, is ascribed to increased soluble SOD1 activity due to the up-regulation of Hsp70 and Hsp27 expression. Conclusively, our results, besides corroborating the anti-inflammatory properties of cyclo(His-Pro), highlight a novel role of the cyclic dipeptide as a proteostasis regulator, and therefore a good candidate for the treatment of ALS and other misfolding diseases.

    更新日期:2018-11-13
  • Interaction of nectin-2α with the auxiliary protein of the voltage-gated A-type K+ channel Kv4.2 dipeptidyl aminopeptidase-like protein at the boundary between the adjacent somata of clustered cholinergic neurons in the medial habenula
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-11-05
    Hajime Shiotani, Muneaki Miyata, Kiyohito Mizutani, Shujie Wang, Akira Mizoguchi, Hideki Mochizuki, Kenji Mandai, Yoshimi Takai

    The medial habenula (MHb) receives septal inputs and sends efferents to the interpeduncular nucleus and is implicated in stress, depression, memory, and nicotine withdrawal syndrome. We previously showed by immunofluorescence microscopy that the cell adhesion molecule nectin-2α is expressed in the cholinergic neurons in the developing and adult mouse MHbs and localized at the boundary between the adjacent somata of clustered cholinergic neurons where the voltage-gated A-type K+ channel Kv4.2 is localized. We further showed by immunoelectron microscopy that Kv4.2 is localized at the membrane specializations (MSs) whereas nectin-2α is localized mostly outside of these MSs. In addition, we showed that genetic ablation of nectin-2 delays the localization of Kv4.2 at the MSs in the developing MHb. We investigated here how nectin-2α regulates this localization of Kv4.2 at the MSs. In vitro biochemical analysis revealed that nectin-2α interacted with the auxiliary protein of Kv4.2 dipeptidyl aminopeptidase-like protein 6 (DPP6), but not with Kv4.2 or another auxiliary protein Kv channel interacting protein 1 (KChIP1). Immunofluorescence microscopy analysis showed that DPP6 was colocalized with nectin-2α at the boundary between the adjacent somata of the clustered cholinergic neurons in the developing and adult MHbs. Immunoelectron microscopy analysis on this boundary revealed that DPP6 was localized both at the inside and the outside of the MSs. Genetic ablation of nectin-2 did not affect the localization of DPP6 at the boundary between the adjacent somata of the clustered cholinergic neurons in the developing and adult MHbs. These results indicate that nectin-2α interacts with DPP6 but regulates the localization of Kv4.2 at the MSs in a DPP6-independent manner.

    更新日期:2018-11-06
  • Strain differences in hippocampal synaptic dysfunction in the TgCRND8 mouse model of Alzheimer's disease: Implications for improving translational capacity
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-11-04
    Wanda M. Snow, Kensuke Oikawa, Jelena Djordjevic, Benedict C. Albensi

    In Alzheimer's disease (AD), characterized by cognitive deterioration, synaptic alterations are frequently reported. The TgCRND8 model, in which mice develop AD-like amyloid β plaque formation, has been used to investigate the effects of amyloidosis on synaptic function. Background strain impacts the behavioral and neuropathological phenotype of mice in this model, but whether this extends to synaptic function is unknown. We investigated the influence of background strain on basal synaptic transmission and long-term potentiation (LTP) in the hippocampus of TgCRND8 mice (13–16 months) on hybrid backgrounds of (129SvEv/Tac) x (C3H/C57/129SvEv/Tac) (aka “129”) or (C57) x (C3H/C57) (aka “C3H”). In littermate controls, basal synaptic transmission was significantly reduced, whereas the amplitude of excitatory postsynaptic potentials was significantly higher after LTP induction in 129 vs. C3H mice. In 129 TgCRND8 mice, deficits in hippocampal LTP were more severe than in C3H TgCRND8 relative to controls. Compared to controls, network excitability was decreased in transgenics from both strains. These data suggest that 129 TgCRND8 mice are the more appropriate model to evaluate the efficacy of potential AD treatments on synaptic function, owing to their significant deficit in LTP. Such studies are critical in order to improve the translational capacity of basic science research.

    更新日期:2018-11-05
  • Biomarkers for diseases with TDP-43 pathology
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-11-03
    Petra Steinacker, Peggy Barschke, Markus Otto

    The discovery that aggregated transactive response DNA-binding protein 43 kDa (TDP-43) is the major component of pathological ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) caused seminal progress in the unveiling of the genetic bases and molecular characteristics of these now so-called TDP-43 proteinopathies. Substantial increase in the knowledge of clinic-pathological coherencies, especially for FTLD variants, could be made in the last decade, but also revealed a considerable complexity of TDP-43 pathology and often a poor correlation of clinical and molecular disease characteristics. To date, an underlying TDP-43 pathology can be predicted only for patients with mutations in the genes C9orf72 and GRN, but is dependent on neuropathological verification in patients without family history, which represent the majority of cases. As etiology-specific therapies for neurodegenerative proteinopathies are emerging, methods to forecast TDP-43 pathology at patients' lifetime are highly required. Here, we review the current status of research pursued to identify specific indicators to predict or exclude TDP-43 pathology in the ALS-FTLD spectrum disorders and findings on candidates for prognosis and monitoring of disease progression in TDP-43 proteinopathies with a focus on TDP-43 with its pathological forms, neurochemical and imaging biomarkers.

    更新日期:2018-11-05
  • A new function for prokineticin 2: Recruitment of SVZ-derived neuroblasts to the injured cortex in a mouse model of traumatic brain injury
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-11-01
    Mayara Vieira Mundim, Laura Nicoleti Zamproni, Agnes Araújo Sardinha Pinto, Layla Testa Galindo, André Machado Xavier, Isaias Glezer, Marimélia Porcionatto
    更新日期:2018-11-05
  • d-Cysteine promotes dendritic development in primary cultured cerebellar Purkinje cells via hydrogen sulfide production
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-10-19
    Takahiro Seki, Masahiro Sato, Ayumu Konno, Hirokazu Hirai, Yuki Kurauchi, Akinori Hisatsune, Hiroshi Katsuki
    更新日期:2018-10-22
  • Validation of reference genes for normalization of real-time quantitative PCR studies of gene expression in brain capillary endothelial cells cultured in vitro
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-10-10
    Maria Hersom, Charlotte Goldeman, Natasia Pretzer, Birger Brodin

    Background The genes encoding β-actin and GAPDH are two of the most commonly used reference genes for normalization in in vitro blood-brain barrier studies. Studies have, however, shown that these reference genes might not always be the best choice. The aim of the present study was to evaluate 10 reference genes for use in mRNA profiling studies in primary cultures of brain endothelial cells of bovine origin. Methods Gene evaluations were performed by qPCR in mono-culture and in co-cultures with astrocytes. The expression of reference genes was furthermore investigated during culture. Qbase+ software was used to analyze the stability of the tested genes and for determinations of the optimal number of reference genes. Results The stability of the reference genes varied between the culture configurations, but for all culture configurations we found that the optimal number of reference genes were two. PMM-1, RPL13A and β-actin were the most stable genes in mono-cultures, non-contact co-culture and contact co-culture respectively. For studies comparing gene expression between different culture configurations the optimal number of reference genes was three and RPL13A was found to be most stable. During cell culture a number of four reference genes were found to be optimal and YWHAZ was found to be the most stable gene. β-actin and GAPDH were found to be the least stable genes during culture. Conclusion Overall we found that the validation of reference genes was important in order to normalize target gene expression correctly, and suggest sets of reference genes to be used under different experimental conditions, in order to quantify mRNA transcript levels in blood-brain barrier cell models correctly.

    更新日期:2018-10-10
  • Reduced retromer function results in the accumulation of amyloid-beta oligomers
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-09-23
    Anna Ansell-Schultz, Juan F. Reyes, My Samuelsson, Martin Hallbeck

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of multiple cognitive functions. Accumulation of amyloid beta oligomers (oAβ) play a major role in the neurotoxicity associated with the disease process. One of the early affected brain regions is the hippocampus, wherein a reduction of the vacuolar protein sorting-associated protein 35 (VPS35), the core protein comprising the retromer complex involved in cellular cargo sorting, has been identified. To investigate the role of the retromer function on the accumulation and clearance of oAβ, we reduced retromer function by selectively inhibiting VPS35 gene expression using siRNA in differentiated neuronal SH-SY5Y cells. As cell-to-cell transfer of oAβ to new brain regions is believed to be important for disease progression we investigated the effect of VPS35 reduction both in cells with direct uptake of oAβ and in cells receiving oAβ from donor cells. We demonstrate that reduced retromer function increases oAβ accumulation in both cell systems, both the number of cells containing intracellular oAβ and the amount within them. This effect was shown at different time points and regardless if the oAβ originated from the extracellular milieu or via a direct neuronal cell-to-cell transfer. Interestingly, not only did reduced VPS35 cause oAβ accumulation, but oAβ treatment alone also lead to a reduction of VPS35 protein content. The accumulated oAβ seems to co-localize with VPS35 and early endosome markers. Together, these findings provide evidence that reduced retromer function decreases the ability for neurons to transport and clear neurotoxic oAβ received through different routes resulting in the accumulation of oAβ. Thus, enhancing retromer function may be a potential therapeutic strategy to slow down the pathophysiology associated with the progression of AD.

    更新日期:2018-09-25
  • Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in β-amyloid overexpressing mice
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-09-22
    Nora E. Gray, Jonathan A. Zweig, Maya Caruso, Jennifer Y. Zhu, Kirsten M. Wright, Joseph F. Quinn, Amala Soumyanath

    Centella asiatica is a medicinal plant used to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates β-amyloid (Aβ)-induced spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its in vivo mechanism of improving Aβ-related cognitive impairment. This study investigates the effects of CAW on learning, memory and executive function as well as mitochondrial function and antioxidant response in the 5xFAD model of Aβ accumulation. Seven month old 5xFAD female mice were treated with CAW (2 mg/mL) in their drinking water for two weeks prior to behavioral testing. Learning, memory and executive function were assessed using the object location memory task (OLM), conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) test. Mitochondrial function was profiled using the Seahorse XF platform in hippocampal mitochondria isolated from these animals and tissue was harvested for assessment of mitochondrial, antioxidant and synaptic proteins. CAW improved performance in all behavioral tests in the 5xFAD but had no effect on WT animals. Hippocampal mitochondrial function was improved and hippocampal and cortical expression of mitochondrial genes was increased in CAW-treated 5xFAD mice. Gene expression of the transcription factor NRF2, as well as its antioxidant target enzymes, was also increased with CAW treatment in both WT and 5xFAD mice. CAW treatment also decreased Aβ-plaque burden in the hippocampus of treated 5xFAD mice but had no effect on plaques in the cortex. These data show that CAW can improve many facets of Aβ-related cognitive impairment in 5xFAD mice. Oral treatment with CAW also attenuates hippocampal mitochondrial dysfunction in these animals. Because mitochondrial dysfunction and oxidative stress accompany cognitive impairment in many pathological conditions beyond Alzheimer's disease, this suggests potentially broad therapeutic utility of CAW.

    更新日期:2018-09-25
  • Effects of gem-dihydroperoxides against mutant copper‑zinc superoxide dismutase-mediated neurotoxicity
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-09-05
    Tomoyuki Ueda, Masatoshi Inden, Yuta Asaka, Yuji Masaki, Hisaka Kurita, Wakako Tanaka, Eiji Yamaguchi, Akichika Itoh, Isao Hozumi

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis, and death. Although its neuropathology is well investigated, currently, effective treatments are unavailable. The mechanism of ALS involves the aggregation and accumulation of several mutant proteins, including mutant copper‑zinc superoxide dismutase (SOD1), TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) proteins. Previous reports have shown that excessive oxidative stress, associated with mitochondrial dysfunction and mutant protein accumulation, contributes to ALS pathology. The present study focuses on the promotion of SOD1 misfolding and aggregation by oxidative stress. Having recently synthesized novel organic gem-dihydroperoxides (DHPs) with high anti-oxidant activity, we now examined whether DHPs reduce the mutant SOD1-induced intracellular aggregates involved in oxidative stress. We found that, among DHPs, 12AC2O significantly inhibited mutant SOD1-induced cell death and reduced the intracellular mutant SOD1 aggregates. Moreover, immunofluorescence staining with redox-sensitive dyes showed that 12AC2O reduced the excessive level of intracellular mutant SOD1-induced reactive oxygen species (ROS). Additionally, ESR analysis showed that 12AC2O exerts a direct scavenging effect against the hydroxyl radical (OH) and the superoxide anion (O2−). These results suggest that 12AC2O is a very useful agent in combination with other agents against ALS.

    更新日期:2018-09-05
  • Deletion of Kir6.2/SUR1 potassium channels rescues diminishing of DA neurons via decreasing iron accumulation in PD
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-08-29
    Qian Zhang, Chengwu Li, Ting Zhang, Yaping Ge, Xiaojuan Han, Sifan Sun, Jianhua Ding, Ming Lu, Gang Hu

    ATP-sensitive potassium (K-ATP) channels express in the central nervous system extensively which coupling cell metabolism and cellular electrical activity. K-ATP channels in mature substantia nigra (SN) dopaminergic (DA) neurons are composed of inwardly rectifying potassium channel (Kir) subunit 6.2 and sulfonylurea receptor 1 (SUR1). Our previous study revealed that regulating K-ATP channel exerts the protective effect on DA neurons in a mouse model of Parkinson's disease (PD). However, the detailed mechanism underlying the role of Kir6.2/K-ATP remains unclear. In the present study, we found the deletion of Kir6.2 dramatically alleviated PD-like motor dysfunction of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD model. We further found that Kir6.2 knockout selectively restored the reduction of both DA neuronal number and dopamine transmitter level in the nigrostriatal of MPTP-treated PD mice. To gain some understanding on the molecular basis of this effect, we focused on the regulation of Kir6.2 deletion on iron metabolism which is tightly associated with DA neuron damage. We found that Kir6.2 knockout suppressed the excessive iron accumulation in MPTP-treated mouse midbrain and inhibited the upregulation of ferritin light chain (FTL), which is a main intracellular iron storage protein. We probed further and found out that the deletion of Kir6.2 inhibited the excessive production of FTL via IRP-IRE regulatory system, and thereby protecting SN DA neurons against MPTP challenge. Our findings suggest that Kir6.2 plays a crucial role in the pathogenesis of PD and regulating Kir6.2/K-ATP channel may be a promising strategy for PD treatment.

    更新日期:2018-08-30
  • 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.

    更新日期:2018-04-10
  • Brain microvascular endothelial-astrocyte cell responses following Japanese encephalitis virus infection in an in vitro human blood-brain barrier model
    Mol. Cell. Neurosci. (IF 3.312) Pub Date : 2018-04-07
    Adjanie Patabendige, Benedict D. Michael, Alister G. Craig, Tom Solomon

    Japanese encephalitis virus (JEV) remains a leading cause of encephalitis, globally, which continues to grow in importance despite the availability of vaccines. Viral entry into the brain can occur via the blood-brain barrier (BBB), and inflammation at the BBB is a common final pathway in many brain infections. However, the role of the BBB during JEV infection and the contribution of the endothelial and astrocytic cell inflammation in facilitating virus entry into the brain are incompletely understood. We established a BBB model using human brain endothelial cells (HBECs) and human astrocytes. HBECs are polarised, and therefore the model was inoculated by JEV from the apical side to simulate the in vivo situation. The effects of JEV on the BBB permeability and release of inflammatory mediators from both apical and basolateral sides, representing the blood and the brain side respectively were investigated. JEV infected HBECs with limited active virus production, before crossing the BBB and infecting astrocytes. Control of JEV production by HBECs was associated with a significant increase in permeability, and with elevation of many host mediators, including cytokines, chemokines, cellular adhesion molecules, and matrix metalloproteases. When compared to the controls, significantly higher amounts of mediators were released from the apical side as opposed to the basolateral side. The increased release of mediators over time also correlated with increased BBB permeability. Treatment with dexamethasone led to a significant reduction in the release of interleukin 6 (IL6), C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) from the apical side with a reduction in BBB disruption and no change in JEV replication. The results are consistent with the hypothesis that JEV infection of the BBB triggers the production of a range of host mediators from both endothelial cells and astrocytes, which control JEV production but disrupt BBB integrity thus allowing virus entry into the brain. Dexamethasone treatment controlled the host response and limited BBB disruption in the model without increasing JEV production, supporting a re-investigation of its use therapeutically.

    更新日期:2018-04-08
  • 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.

    更新日期:2018-04-08
  • 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.

    更新日期:2018-04-08
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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华中师范大学化学生物学中心招聘化学类博士后
哈尔滨工业大学刘绍琴教授课题组诚招博士后、科研助理
南方科技大学讲座教授郑智平团队——行政秘书招聘启事
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