Roles of the CSPalpha Chaperone Complex in Presynaptic Maintenance and ANCL

描述（由申请人提供）：突触需要在一生中积极维护，以提供稳定的神经网络，从而提供正常的大脑功能。临床研究结果强烈表明，在常见的脑部疾病中，如智力迟钝、精神分裂症、阿尔茨海默病和帕金森病，突触维持被破坏。尽管其重要性，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¿是一种突触前共同伴侣，是少数被确定对突触稳定性至关重要的基因之一。CSP¿结合热休克同源物70 （Hsc70）在突触囊泡上形成功能性伴侣复合物。这种伴侣复合物被假设折叠对突触稳定性至关重要的突触前蛋白。CSP¿对人类健康的重要性被最近在成人发病的神经元类蜡质脂褐质病（ANCL）中发现的CSP¿突变所强调，ANCL是一种具有溶酶体病理的主要神经退行性疾病。在本提案中，我们的目标是基于无偏蛋白质组学筛选来剖析CSP¿突触维持途径，该筛选成功地鉴定了CSP¿/Hsc70伴侣复合物的蛋白质底物。在这里，我们的目的是表征这些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。这些实验将勾勒出脊椎动物突触前维持通路，并阐明ANCL的机制。鉴于具有突触丧失和功能障碍的脑疾病范围广泛，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.