Roles of the CSPalpha Chaperone Complex in Presynaptic Maintenance and ANCL

CSPalpha 伴侣复合物在突触前维持和 ANCL 中的作用

• 批准号: 9222810
• 负责人: Sreeganga S Chandra
• 金额: $ 36.42万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222810
• 关键词: Adult; Alzheimer' s Disease; Behavior; Binding; Biochemical; Biochemistry; Biology; Biotin; Brain; Brain Diseases; Ceroid; Chemistry; Client; Clinical; Collaborations; Communication; Complex; Coupling; Data; Disease; Dominant-Negative Mutation; Drosophila genus; Dynamin; Dynamin I; Electron Microscopy; Endocytosis; Exhibits; Functional disorder; Gap Junctions; Genes; Genetic; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Heat shock proteins; Heat-Shock Response; Hsc70 protein; Human; Impairment; Knock-out; Knockout Mice; Knowledge; Life; Link; Lysosomes; Maintenance; Mental Retardation; Methods; Modeling; Molecular; Molecular Chaperones; Molecular Conformation; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Ceroid-Lipofuscinosis; Neuronal Dysfunction; Neurons; Parkinson Disease; Pathology; Pathway interactions; Patients; Pattern; Phenocopy; Proteins; Proteomics; Recruitment Activity; Recycling; Research; Role; S-nitro-N-acetylpenicillamine; Schizophrenia; Site; Substrate Interaction; Synapses; Synaptic Vesicles; Testing; Therapeutic Intervention; Vertebrates; base; biophysical analysis; cysteine string protein; density; experimental study; fly; gain of function; in vitro testing; in vivo; insight; loss of function; mutant; nervous system disorder; neurodegenerative phenotype; neuronal cell body; palmitoylation; presynaptic; protein aggregate; proteostasis; public health relevance; reconstitution; synaptogyrin; target SNARE proteins

DESCRIPTION (provided by applicant): Synapses need to be actively maintained throughout life to provide for stable neuronal networks and hence normal brain functions. Clinical findings strongly suggest that synapse maintenance is disrupted in common brain disorders, such as mental retardation, schizophrenia, Alzheimer's and Parkinson's disease. Despite its importance, the pathways that control synapse maintenance remain to be defined at a molecular level. Our long term goal is to elucidate the molecular basis of synapse maintenance. CSP�, a presynaptic co-chaperone, is one of the few genes identified to be essential for synapse stability. CSP� binds Heat Shock Cognate 70 (Hsc70) to form a functional chaperone complex on synaptic vesicles. This chaperone complex has been hypothesized to fold presynaptic proteins critical for synaptic stability. The importance of CSP� for human health is underscored by the recent identification of CSP� mutations in adult-onset neuronal ceroid-lipofuscinosis (ANCL), a dominant neurodegenerative disorder with lysosomal pathology. In this proposal, we aim to dissect the CSP� synapse maintenance pathway based on an unbiased proteomic screen that successfully identified protein substrates of the CSP�/Hsc70 chaperone complex. Here, we aim to characterize these CSP�/Hsc70 protein substrates and determine their functions in synaptic stability. Then, we will examine the mechanisms of CSP� dysfunction in ANCL. In particular, we will investigate the role of aberrant protein palmitoylation and CSP�/Hsc70 protein substrate degradation in this disease. These experiments will delineate the first presynaptic maintenance pathway in vertebrates and elucidate the mechanisms of ANCL. Achieving these goals is important for human health, given the wide range of brain disorders that have synaptic loss and dysfunction.

描述（由申请人提供）：突触需要在一生中积极维护，以提供稳定的神经元网络，从而提供正常的大脑功能。临床研究结果强烈表明，常见脑部疾病（例如智力低下、精神分裂症、阿尔茨海默氏症和帕金森氏症）中突触的维持受到破坏。尽管其重要性，控制突触维持的途径仍有待在分子水平上定义。我们的长期目标是阐明突触维持的分子基础。 CSP� 是一种突触前共伴侣，是少数被确定对突触稳定性至关重要的基因之一。 CSP� 结合热休克同源 70 (Hsc70)，在突触小泡上形成功能性伴侣复合物。据推测，这种伴侣复合物可以折叠对突触稳定性至关重要的突触前蛋白。最近在成人发病的神经元蜡样脂褐质沉着症 (ANCL) 中发现了 CSP� 突变，突显了 CSP� 对人类健康的重要性，ANCL 是一种具有溶酶体病理学的显性神经退行性疾病。在本提案中，我们的目标是基于无偏蛋白质组筛选来剖析 CSP� 突触维持途径，该筛选成功鉴定了 CSP�/Hsc70 伴侣复合物的蛋白质底物。在这里，我们的目标是表征这些 CSP�/Hsc70 蛋白底物并确定它们在突触稳定性中的功能。然后，我们将研究 ANCL 中 CSP 功能障碍的机制。特别是，我们将研究异常蛋白棕榈酰化和 CSP�/Hsc70 蛋白底物降解在该疾病中的作用。这些实验将描绘脊椎动物中第一个突触前维持通路并阐明 ANCL 的机制。鉴于导致突触丧失和功能障碍的大脑疾病种类繁多，实现这些目标对人类健康非常重要。