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Nonproteolytic Polyubiquitin Chains at the Synapse

突触的非蛋白水解多聚泛素链

基本信息

批准号：
9438416
负责人：
Wei-Dong Yao
金额：
$ 40.76万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9438416
关键词：
Adult Anxiety Autistic Disorder Behavioral Biochemical Biological Assay Brain Brain Diseases Chemicals Cognitive Dendritic Spines Deubiquitinating Enzyme Development Disease Electrophysiology (science)Emotional Enzymes Goals In Vitro Injury Investigation Link Long-Term Depression Lysine Maintenance Mediating Memory Modification Molecular Motivation Mus Mutant Strains Mice Natural Immunity Neuraxis Neurodegenerative Disorders Neurodevelopmental Disorder Neuroimmune Neurons Pathway interactions Phenotype Physiological Polyubiquitin Polyubiquitination Prefrontal Cortex Process Property Proteins Psychomotor Performance Rattus Regulation Rewards Role Scaffolding Protein Schizophrenia Short-Term Memory Signal Transduction Slice Synapses System TNF Receptor-Associated Factors TRAF6 gene Testing Transgenic Mice Ubiquitin Ubiquitination adaptive immunity autism spectrum disorder behavior test behavioral impairment brain abnormalities cellular imaging experimental study in vivo long term memory multicatalytic endopeptidase complex multidisciplinary nervous system disorder neural circuit neuropsychiatric disorder novel postsynaptic pre-clinical protein degradation public health relevance repaired response scaffold social cognition synaptogenesis trafficking treatment strategy ubiquitin-protein ligase virtual

项目摘要

DESCRIPTION (provided by applicant): Altered assembly, function, and plasticity of synapses and neural circuits underlie cognitive, memory, and emotional deficits of essentially all neuropsychiatric and neurological diseases. A well-investigated mechanism that regulates synaptic protein turnover and synapse remodeling is the conventional ubiquitin-proteasome pathway, by which polyubiquitin chains conjugate to protein substrates (likely through lysine 48 (K48) of ubiquitin) and tag them for proteasomal degradation. A vastly overlooked ubiquitin modification in the central nervous system (CNS) is K63-linked polyubiquitination, an unconventional linkage mechanism generally believed not to target proteasomal degradation; rather, it regulates protein scaffolding, trafficking, and activity. Despite its recognized importace in cellular signaling mechanisms that mediate innate and adaptive immunity, virtually nothing is known about the role of this proteasome-independent polyubiquitination process in the CNS, especially synapses. Nonetheless, K63-linked ubiquitination is the second most abundant linkage in the rat brain, only slightly behind the K48 linkage. In addition, emerging evidence points to a link between K63-linked ubiquitination and a number of brain disorders. Thus, there is a need to investigate the mechanisms and roles of this nonproteolytic polyubiquitin topology in neurons and at synapse. Our preliminary studies indicate that K63-linked polyubiquitination is a fundamental mechanism regulating synapse assembly and plasticity and identify the postsynaptic scaffolding protein PSD-95 as the first substrate. We also identify a PSD-associated, K63-linkage-specific enzyme machinery that controls PSD-95 ubiquitination at synapses. The goals of this R01 application are to define the molecular details and functional consequences of PSD-95 K63 polyubiquitination (Aim 1), to delineate the role of K63 polyubiquitination in synapse development, function, remodeling, and plasticity (Aim 2), and to characterize the behavioral alterations in mice lacking K63-linkage-specific E3 ubiquitin ligase TRAF6 and deubiquitinase CYLD (Aim 3). A combination of molecular, biochemical, electrophysiological, and behavioral approaches will be employed. The proposed studies represent a fundamentally important conceptual breakthrough that opens up new avenues for investigation of synapse and circuit function and plasticity. The project has the potential to uncover new paradigm-shifting principles that govern neuro-immune interactions, which may contribute to abnormal brain wiring in neurodevelopmental disorders (such as schizophrenia and autism spectrum disorders) and neural circuit repair in the adult brain following injury. The information obtained will facilitate development of novel treatment strategies for these brain disorders.