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.

Public Health Relevance

Synapses, sites of communication between neurons, need to be preserved throughout life to allow for normal brain functions and behavior. Aberrant synapse maintenance is linked to mental retardation, schizophrenia, and neurodegenerative diseases. In this study, we will characterize CSPa, a gene that is essential for the maintenance of synapses and examine its dysfunction in disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS083846-01A1
Application #
8696912
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Morris, Jill A
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$364,569
Indirect Cost
$132,668
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Vargas, Karina J; Makani, Sachin; Davis, Taylor et al. (2014) Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci 34:9364-76
Zhang, Yong-Quan; Chandra, Sreeganga S (2014) Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1842:2136-46