We recently discovered that various Parkinson-related proteins, including parkin, DJ-1, andprotein-disulfide isomerase (PDI), are S-nitrosylated and then further oxidized (published inPNAS, Science, and Nature). S-Nitrosylation (chemical transfer of an NO group to a criticalcysteine thiol) affects protein function - in the case of parkin, regulating its E3 ligase activity; forPDI contributing to protein misfolding; and for DJ-1, possibly affecting DJ-1 dimerization or itsinteractions 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 reactionsappear to contribute to the pathogenesis of Parkinson's disease. Here, we will further study thesenitrosylation reactions with the Proteomics Core (Core B), seek structural evidence for their basiswith the Structural Core (Core C), and perform high-throughput screening with our ChemicalLibrary Core (Core E) to develop novel drugs that prevent these nitrosylation reactions and thatare therefore potentially neuroprotective. These drugs will be tested subsequently within thisproject 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 AnimalBehavior Core (Core D).
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