Journal of Experimental Neuroscience最新文献

{"title":"Sorting Out the Role of α-Synuclein in Retromer-Mediated Endosomal Protein Sorting.","authors":"Dhaval Patel,&nbsp;Stephan N Witt","doi":"10.1177/1179069518796215","DOIUrl":"https://doi.org/10.1177/1179069518796215","url":null,"abstract":"<p><p>Retromer is a phylogenetically conserved, multisubunit coat complex that controls endosomal protein trafficking and sorting. Mutations in the retromer gene <i>VPS35</i> cause late-onset Parkinson disease, suggesting that trafficking defects cause neurodegeneration. Sorting nexins assist retromer to guide cell surface proteins to their assigned destinations, and our interest here is sorting nexin 3 (Snx3). Snx3 binds to membranes via a phox homolog (PX) domain that binds phosphatidylinositol 3-phosphate (PI3P), and in human cells its cargo proteins are the transferrin and Wnt receptors and the divalent metal ion transporter, whereas in yeast the best characterized cargo is the iron permease Ftr1. We recently discovered that α-synuclein inhibits Snx3-retromer recycling of Ftr1 in an unexpected way: α-synuclein, which avidly binds to negatively charged lipids, blocks the association of Snx3 to early endosomes. Here, we discuss mechanisms by which α-synuclein can disrupt Snx3-retromer-mediated recycling.</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518796215"},"PeriodicalIF":0.0,"publicationDate":"2018-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518796215","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36443346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing Lysosomal Activation Restores Neural Stem Cell Function During Aging.","authors":"Amanda J Audesse,&nbsp;Ashley E Webb","doi":"10.1177/1179069518795874","DOIUrl":"https://doi.org/10.1177/1179069518795874","url":null,"abstract":"<p><p>Adult neurogenesis supports cognitive and sensory functions in mammals and is significantly reduced with age. Quiescent neural stem cells are the source of new neurons in the adult brain and emerging evidence suggests that the failure of these cells to activate and re-enter the cell cycle is largely responsible for reduced neurogenesis in old animals. However, the molecular mechanisms supporting quiescence and activation in the adult and aged brain remain undefined. Recent work published by Leeman et al. in <i>Science</i> uncovers a novel role for lysosomes in supporting neural stem cell activation, and reveals that loss of lysosome function during aging contributes to reduced neural stem cell activity. Using a combination of transcriptomics and functional analysis, the authors show that quiescent and activated neural stem cells employ different branches of proteostasis networks, with quiescent stem cells particularly dependent on the lysosome-autophagy system. Excitingly, stimulation of lysosomal activity in the aged quiescent population significantly enhanced their ability to activate and increased the frequency of activated neural stem and progenitor cells within the neural stem cell niche. This work for the first time identifies lysosomal dysfunction as a cause of reduced neurogenesis during aging, and shows that enhancing lysosomal function is sufficient to restore healthy stem cell activity in the aged brain.</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518795874"},"PeriodicalIF":0.0,"publicationDate":"2018-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518795874","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36443345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of Oxidative Phosphorylation-Related Genes With Deep Intracerebral Hemorrhage in Taiwan.","authors":"Yi-Chun Chen,&nbsp;Chiung-Mei Chen,&nbsp;Yun-Shien Lee,&nbsp;Kuo-Hsuan Chang","doi":"10.1177/1179069518794517","DOIUrl":"https://doi.org/10.1177/1179069518794517","url":null,"abstract":"<p><strong>Background: </strong>Pathway analysis demonstrated associations between deep intracerebral hemorrhage (DICH) and the genetic risk score of complex IV of the oxidative phosphorylation (OXPHOS) pathway in whites. This study investigated the related genetic variations in the DICH population in Taiwan. Candidate variants were selected from the prior report by the following criteria: (1) nuclear genes encoding mitochondria complex IV, (2) genetic effect >1.08, (3) global minor allele frequency >0.01. Six single-nucleotide polymorphisms fitted in the selection criteria, which were mainly involved in Cox assembly, including Cox10, Cox15, and Cox18, and one structural gene, Cox7C. Associations were tested with adjustment of multiple covariables. Permutation testing of 1000 replicates was performed for empirical estimates.</p><p><strong>Results: </strong>This study enrolled 336 patients and 379 controls. Compared with whites, the Taiwan population has higher minor allele frequency (MAF) of rs4308511, rs767844, and rs221592 and lower MAF of rs8079640. There was no variation of rs16949067 in the Taiwan population. When adjusting for the traditional risk factors, rs221592 G allele was associated with DICH risk in women under additive (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.02-2.3, <i>P</i> = .04) and recessive models (OR = 2.9, 95% CI = 1.2-6.9, <i>P</i> = .013). In an additive fashion, a poor 30-day outcome was associated with rs4308511 T allele (OR = 1.6, 95% CI = 1.1-2.3, <i>P</i> = .014) and rs9891372 C allele (OR = 1.7, 95% CI = 1.05-2.8, <i>P</i> = .024) in all subjects and in men (rs4308511, OR = 1.8, 95% CI = 1.2-2.7, <i>P</i> = .008; rs9891372, OR = 2.1, 95% CI = 1.1-3.8, <i>P</i> = .02).</p><p><strong>Conclusions: </strong>The results showed ethnic disparities in the complex IV-related genes. COX18-rs221592 G allele was associated with female DICH risks. COX7C-rs4308511 T allele was an independent risk of poor outcome in men.</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518794517"},"PeriodicalIF":0.0,"publicationDate":"2018-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518794517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36434987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Could a Common Mechanism of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases?","authors":"David M Smith","doi":"10.1177/1179069518794675","DOIUrl":"https://doi.org/10.1177/1179069518794675","url":null,"abstract":"<p><p>At the cellular level, many neurodegenerative diseases (NDs), often considered proteinopathies, are characterized by the accumulation of misfolded and damaged proteins into large insoluble aggregates. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are amyloid β (Aβ) and tau in Alzheimer disease, α-synuclein (α-syn) in Parkinson disease, and polyQ-expanded huntingtin (Htt) in Huntington disease. Although significant efforts have focused on how the cell deals with these protein aggregates, why is it that these misfolded proteins are not degraded normally in the first place? A vast body of literature supports the notion that the cell's protein degradation system for individual proteins-the ubiquitin proteasome system (UPS)-does not function sufficiently in many NDs. The proteasome itself has received significant focus for years due to its obvious failure to degrade misfolded proteins in ND, but no general mechanism has been uncovered. We have recently found that specific pathologically relevant oligomers can potently and directly inhibit the proteasome. What is most interesting is that the misfolded protein's primary amino acid sequence was irrelevant to its ability to inhibit. Instead, the culprit is the 3-dimensional shape of the misfolded oligomers. It turns out that many misfolded proteins in ND can take on this proteasome-impairing shape suggesting that there could be a common mechanism for UPS impairment in many NDs. The proteasome is already an important target for treating cancer, could it also be targeted to broadly treat ND?</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518794675"},"PeriodicalIF":0.0,"publicationDate":"2018-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518794675","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36429556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALK and GSK3: Shared Features of Neuroblastoma and Neural Crest Cells.","authors":"Sandra G Gonzalez Malagon,&nbsp;Karen J Liu","doi":"10.1177/1179069518792499","DOIUrl":"https://doi.org/10.1177/1179069518792499","url":null,"abstract":"<p><p>Neuroblastoma is one of the most common and deadly childhood cancers. Neuroblastoma arises from transformed cells of the neural crest lineage. Outcomes of the disease vary greatly, ranging from spontaneous regression to aggressive metastases. While this variability may reflect the inherent migratory capabilities and multipotency of neural crest cells, there have been few direct comparisons between neuroblastoma and embryonic neural crest cells, in part because of the limited in vivo accessibility of the mammalian neural crest lineage. Our recent studies demonstrate a novel link between anaplastic lymphoma kinase (ALK) and glycogen synthase kinase 3 (GSK3). Our work suggests that ALK-dependent regulation of GSK3 via tyrosine phosphorylation may alter the substrate specificity of GSK3, thus regulating cytoskeletal dynamics in migrating neural crest cells.</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518792499"},"PeriodicalIF":0.0,"publicationDate":"2018-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518792499","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36414856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Integrative Approach to Neuroinflammation in Psychiatric disorders and Neuropathic Pain.","authors":"Diana I Lurie","doi":"10.1177/1179069518793639","DOIUrl":"https://doi.org/10.1177/1179069518793639","url":null,"abstract":"<p><p>Neuroinflammation is a complex process involving both the peripheral circulation and the Central Nervous System (CNS) and is considered to underlie many CNS disorders including depression, anxiety, schizophrenia, and pain. Stressors including early-life adversity, psychosocial stress, and infection appear to prime microglia toward a pro-inflammatory phenotype. Subsequent inflammatory challenges then drive an exaggerated neuroinflammatory response involving the upregulation of pro-inflammatory mediators that is associated with CNS dysfunction. Several pharmacologic inhibitors of pro-inflammatory cytokines including TNF-α and IL-1β show good clinical efficacy in terms of ameliorating neuroinflammatory processes. Mind/body and plant-based interventions such as yoga, breathing exercises, meditation, and herbs/spices have also been demonstrated to reduce pro-inflammatory cytokines and have a positive impact on depression, anxiety, cognition, and pain. As the intricate connections between the immune system and the nervous system continue to be elucidated, successful therapies for reducing neuroinflammation will likely involve an integrated approach combining drug therapy with nonpharmacologic interventions.</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518793639"},"PeriodicalIF":0.0,"publicationDate":"2018-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518793639","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36414857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of Innate Defensive Responses by Locus Coeruleus-Superior Colliculus Circuit.","authors":"Lei Li,&nbsp;Liping Wang","doi":"10.1177/1179069518792035","DOIUrl":"https://doi.org/10.1177/1179069518792035","url":null,"abstract":"<p><p>Among key survival circuits, defensive response circuits are one of the most intensively studied. A consensus is emerging that multiple, independent circuitries are involved in different conditioned and unconditioned defensive responses. Investigating these well-conserved defensive responses would help us to decipher the basic working mechanism of the brain at a circuitry level and thus shed light on new diagnoses and treatments for neural diseases and disorders. We showed that the visually evoked innate defensive response was modulated by a locus coeruleus-superior colliculus (LC-SC) projection. Our work demonstrates that as conserved and instinctive as the survival circuits are, they are flexible and subject to fine-tuned modulation by experience or internal states of the animals. Here, we provide more data to further discuss the possible downstream mechanisms of the LC-SC pathway for this important modulation of the defensive response, the wide range of flight latency between individual flight responses, and the interpretations of our data with additional statistical analysis.</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518792035"},"PeriodicalIF":0.0,"publicationDate":"2018-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518792035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36414855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Monoamines and Antidepressants on Astrocyte Physiology: Implications for Monoamine Hypothesis of Depression.","authors":"Swananda V Marathe,&nbsp;Priyal L D'almeida,&nbsp;Garima Virmani,&nbsp;Praveen Bathini,&nbsp;Lavinia Alberi","doi":"10.1177/1179069518789149","DOIUrl":"https://doi.org/10.1177/1179069518789149","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders affecting over one-fifth of the population worldwide. Owing to our limited understanding of the pathophysiology of MDD, the quest for finding novel antidepressant drug targets is severely impeded. Monoamine hypothesis of MDD provides a robust theoretical framework, forming the core of a large jigsaw puzzle, around which we must look for the vital missing pieces. Growing evidence suggests that the glial loss observed in key regions of the limbic system in depressed patients, at least partly, accounts for the structural and cognitive manifestations of MDD. Studies in animal models have subsequently hinted at the possibility that the glial atrophy may play a causative role in the precipitation of depressive symptoms. Antidepressants as well as monoamine neurotransmitters exert profound effects on the gene expression and metabolism in astrocytes. This raises an intriguing possibility that the astrocytes may play a central role alongside neurons in the behavioral effects of antidepressant drugs. In this article, we discuss the gene expression and metabolic changes brought about by antidepressants in astrocytes, which could be of relevance to synaptic plasticity and behavioral effects of antidepressant treatments.</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518789149"},"PeriodicalIF":0.0,"publicationDate":"2018-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518789149","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36344977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic Interaction Between Microtubules and the Nucleus Regulates Nuclear Movement During Neuronal Migration.","authors":"You Kure Wu,&nbsp;Mineko Kengaku","doi":"10.1177/1179069518789151","DOIUrl":"https://doi.org/10.1177/1179069518789151","url":null,"abstract":"<p><p>Fine structures of the mammalian brain are formed by neuronal migration during development. Newborn neurons migrate long distances from the germinal zone to individual sites of function by squeezing their largest cargo, the nucleus, through the crowded neural tissue. Nuclear translocation is thought to be orchestrated by microtubules, actin, and their associated motor proteins, dynein and myosin. However, where and how the cytoskeletal forces are converted to actual nuclear movement remains unclear. Using high-resolution confocal imaging of live migrating neurons, we demonstrated that microtubule-dependent forces are directly applied to the nucleus via the linker of nucleoskeleton and cytoskeleton complex, and that they induce dynamic nuclear movement, including translocation, rotation, and local peaking. Microtubules bind to small points on the nuclear envelope via the minus- and plus-oriented motor proteins, dynein and kinesin-1, and generate a point force independent of the actin-dependent force. Dynamic binding of microtubule motors might cause a continuously changing net force vector acting on the nucleus and results in a stochastic and inconsistent movement of the nucleus, which are seen in crowded neural tissues.</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518789151"},"PeriodicalIF":0.0,"publicationDate":"2018-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518789151","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36325492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Memory System Neurons Represent Gaze Position and the Visual World.","authors":"Miriam Meister","doi":"10.1177/1179069518787484","DOIUrl":"10.1177/1179069518787484","url":null,"abstract":"<p><p>The entorhinal cortex, a brain area critical for memory, contains neurons that fire when a rodent is in a certain location (eg, grid cells), or when a monkey looks at certain locations. In rodents, these spatial representations align to visual objects in the environment by firing when the animal is in a preferred location defined by relative position of visual environmental features. Recently, our laboratory found that simultaneously recorded entorhinal neurons in monkeys can exhibit different spatial reference frames for gaze position, including a reference frame of visual environmental features. We also discovered that most of the neurons represent gaze position. These results suggest that gaze information in multiple spatial reference frames is a potent signal used in the primate memory system. Here, I describe how these findings support three underappreciated views of the hippocampal memory system.</p>","PeriodicalId":15817,"journal":{"name":"Journal of Experimental Neuroscience","volume":"12 ","pages":"1179069518787484"},"PeriodicalIF":0.0,"publicationDate":"2018-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1179069518787484","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36333627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}