Mutations in parkin are largely associated with autosomal recessive juvenile parkinsonism (AR-JP). The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity leading to accumulation of parkin substrates due to failure of the ubiquitin proteasome system. A large number of possible parkin substrates have been identified, yet their role in the pathogenesis of PD due to parkin mutations have yet to be clarified. Moreover, the post-translational modifications that potentially regulate parkin's function are not known. We propose to generate and characterize parkin knockout mice to test the role of proteasome dysfunction in PD. Furthermore, we propose to characterize and identify parkin substrates, and identify potential post-translational modifications of parkin that regulate its function, thus providing important new information about the role of UPS dysfunction in PD. To accomplish these goals we propose the following specific aims.
In Specific Aim #1 we will generate and characterize parkin knockout mice.
In Specific Aim #2 we will evaluate the sensitivity of parkin knockouts to proteasome inhibitors.
In Specific Aim #3 we will characterize the Role of Nitrosative Stress on Parkin Function.
In Specific Aim #4 we will identify additional and potentially authentic parkin substrates in parkin knockout mice in response to proteasome inhibition. Identification and characterization of parkin substrates and regulatory mechanisms of parkin function may provide novel therapeutics and targets to prevent the toxic effects of this familial associated gene in the degenerative process of PD.
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