Roles of the CSPalpha Chaperone Complex in Presynaptic Maintenance and ANCL

描述(申请人提供)：突触需要在一生中积极维持，以提供稳定的神经元网络，从而提供正常的大脑功能。临床研究结果有力地表明，在常见的大脑疾病中，突触的维持被破坏，如智力低下、精神分裂症、阿尔茨海默氏症和帕金森氏症。尽管它很重要，但控制突触维持的途径仍然在分子水平上被定义。我们的长期目标是阐明突触维持的分子基础。CSP？是一种突触前辅助伴侣，是少数几个对突触稳定性至关重要的基因之一。CSP与热休克蛋白70(Hsc70)结合，在突触小泡上形成功能性伴侣复合体。这种伴侣复合体被假设为折叠对突触稳定性至关重要的突触前蛋白。最近在成人型神经元蜡样脂褐素沉着症(ANCL)中发现了CSP突变，这是一种具有溶酶体病理的显性神经退行性疾病，突显了CSP对人类健康的重要性。在这项提案中，我们的目标是基于一项无偏见的蛋白质组筛选，成功地确定CSP？/Hsc70伴侣复合体的蛋白质底物，剖析CSP？突触维持途径。在这里，我们的目标是鉴定这些CSP？/Hsc70蛋白底物，并确定它们在突触稳定性中的功能。然后，我们将探讨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蛋白底物降解在该病中的作用。这些实验将描绘脊椎动物第一条突触前维持通路，并阐明ANCL的机制。考虑到各种具有突触丢失和功能障碍的大脑疾病，实现这些目标对人类健康非常重要。

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.