CSP? regulation of exo-endocytic cycle enhances synaptic stability. Synapses are intricate structures that undergo structural modifications constantly. In healthy brains, synapses are maintained by activity-dependent mechanisms. These processes are compromised in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, leading to profound synapse loss early in disease progression. The purpose of this project is to investigate presynaptic mechanisms of synapse maintenance using a mouse lacking the co-chaperone cysteine string protein ? (CSP?). The nervous system of this mouse develops normally, however synapses are rapidly lost after maturation of the mouse, leading to gross neurodegeneration and early death. We have performed an unbiased screen for CSP? clients, which indicates that CSP? is interacting with select proteins involved in synaptic vesicle exo- and endocytosis. We therefore hypothesize that CSP? stabilizes synapses by regulating the exo-endocytic cycling of synaptic vesicles and interacting with the presynaptic cytoskeleton. I will test our hypothesis by first examining activity-dependent synaptic vesicle cycling using stimulated neuron cultures, endocytic labeling and electron microscopic analysis. Next, I will establish an expanded list of CSP? client proteins using pulldown experiments followed by proteomic analysis. Finally, using the list of client proteins, I will test whether any single client or a combination of clients are able to modify the synapse loss phenotype observed in CSP? knockout neurons using overexpression and knockdown techniques. This study will provide insight into how synapses are maintained in healthy nervous systems and how synapses are lost in neurodegenerative diseases.

Public Health Relevance

Neurodegenerative diseases are devastating for both patients and caretakers alike and will continue to affect an exponentially expanding portion of the population without novel therapeutics. A common denominator of neurodegenerative diseases is protein misfolding. By investigating an essential mechanism that assists synaptic protein folding, this project will characterize a novel pathway for prevention of neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS078861-01
Application #
8312242
Study Section
Special Emphasis Panel (ZRG1-F03A-N (20))
Program Officer
Stewart, Randall R
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$27,244
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520