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Inappropriate Intrusion of Syntaphilin into Dendrites Kills Neurons in Pathology

Syntaphilin 不恰当地侵入树突会杀死病理学中的神经元

基本信息

批准号：
9413271
负责人：
SHING Yan CHIU
金额：
$ 22.95万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9413271
关键词：
3-Dimensional Animal Model Animals Axon Binding Categories Cell Death Cerebellar Diseases Cerebellar degeneration Cerebellum Cessation of life Color Congestive Coupled Coupling Dendrites Disease model Etiology Event Fluorescence Future Genetic Goals Image Image Analysis Immobilization Immunohistochemistry In Vitro Link Mediating Methodology Methods Microfluidics Mitochondria Mitochondrial Proteins Modeling Molecular Morphologic artifacts Multiple Sclerosis Mus Nerve Degeneration Neurodegenerative Disorders Neurons Pathologic Pathology Property Proteins Published Comment Publishing Purkinje Cells Regulation Reporting Role Shivering Specificity Spinocerebellar Ataxias Synapses Time Up-Regulation Variant Vertebral column Viral Work axon injury base design dysmyelination excitotoxicity exhaustion experimental study high resolution imaging in vivo multiple sclerosis treatment neuron loss neuroprotection novel overexpression presynaptic prevent recruit success syntaphilin

项目摘要

Project Summary The premise of this R21 is that we overlooked a dendritic event in our recent, axon-focus study on cerebellar degeneration in the dysmyelinating Shiverer mouse (Joshi et al., 2015). In the Shiverer cerebellum, we found a parallel increase in SNPH and two forms of cerebellar neurodegeneration, Purkinje cell death and axonal injury, and that genetic deletion of SNPH protects both forms of neurodegeneration. Because SNPH is an axon-specific anchor for mitochondria, we focused our 2015 study on axons and proposed that SNPH upregulation at axons causes mitochondrial traffic congestion that first kills axons then secondarily leads to neuronal death. Deletion of SNPH is protective primarily by preventing axonal death. However, when we re- examined the dendritic layers of Purkinje cells in the Shiverer cerebellum intermingled with densely packed presynaptic axons with the expected upregulation of SNPH, we discovered upon careful 3-D confocal examination that SNPH regulation also occurs in dendrites. This is a total surprise, and may constitute the first demonstrated case that this prominent, axon-specific mitochondrial anchor can lose spatial specificity in pathology and intrudes into the dendritic compartment. The goal of this R21 is to examine if dendritic SNPH intrusion has pathologic consequences that independently kill neurons unrelated to axonal injury. In Aim #1, we will use complementary molecular approaches in addition to the standard 3-D confocal methodology to prove that dendritic SNPH intrusion is not an artifact. In Aim #2, we will demonstrate that dendritic SNPH intrusion is not an innocuous epiphenomenon but can sensitize neurons to excitotoxicity. Conclusion - Given the novelty of this discovery we designed the two aims to be very limited in scope: Eliminating Artifact in Aim #1 and Establishing Causality in Aim #2. Success will engender a future RO1 to elucidate mechanisms of how dendritic SNPH intrusion kills neurons, possibly opening up a completely new category of dendritic pathology in the field of neurodegenerative diseases.

项目总结