We recently discovered that various Parkinson-related proteins, including parkin, DJ-1, and protein-disulfide isomerase (PDI), are S-nitrosylated and then further oxidized (published in PNAS, Science, and Nature). S-Nitrosylation (chemical transfer of an NO group to a critical cysteine thiol) affects protein function - in the case of parkin, regulating its E3 ligase activity;for PDI contributing to protein misfolding;and for DJ-1, possibly affecting DJ-1 dimerization or its interactions with PINK1 and thus the stability of the parkin/PINK1/DJ-1 complex (as shown by Dr. Z. Zhang in Project 1 of this NIEHS Center Grant Application). These S-nitrosylation reactions appear to contribute to the pathogenesis of Parkinson's disease. Here, we will further study these nitrosylation reactions with the Proteomics Core (Core B), seek structural evidence for their basis with the Structural Core (Core C), and perform high-throughput screening with our Chemical Library Core (Core E) to develop novel drugs that prevent these nitrosylation reactions and that are therefore potentially neuroprotective. These drugs will be tested subsequently within this project in secondary screens for neuronal survival on primary neurons in vitro here in Project 3, and in mouse transgenic (tg) models of PD in conjunction with the Neuropathology and Animal Behavior Core (Core D).

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES016738-05
Application #
8377578
Study Section
Special Emphasis Panel (ZES1-LWJ-G)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$311,296
Indirect Cost
$139,894
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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