Roles of the CSPalpha Chaperone Complex in Presynaptic Maintenance and ANCL

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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. CSPα, a presynaptic co-chaperone, is one of the few genes identified to be essential for synapse stability. CSPα 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 CSPα for human health is underscored by the recent identification of CSPα mutations in adult-onset neuronal ceroid-lipofuscinosis (ANCL), a dominant neurodegenerative disorder with lysosomal pathology. In this proposal, we aim to dissect the CSPα synapse maintenance pathway based on an unbiased proteomic screen that successfully identified protein substrates of the CSPα/Hsc70 chaperone complex. Here, we aim to characterize these CSPα/Hsc70 protein substrates and determine their functions in synaptic stability. Then, we will examine the mechanisms of CSPα dysfunction in ANCL. In particular, we will investigate the role of aberrant protein palmitoylation and CSPα/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.