Mutations in the parkin gene leading to a loss in its normal function result in early onset Parkinson's Disease with an autosomal recessive pattern of inheritance. Parkin has been shown to be an enzyme involved in the ubiquitin-proteasome pathway for degradation of cellular proteins. Parkin not only has a molecular domain associated with ubiquitin-protein ligase activity, but is one of few large proteins to contain a region with homology to the ubiquitin peptide. This rare domain has been identified in proteins that bind molecular chaperones and the proteasome. Our preliminary work has demonstrated that parkin can reverse the harmful effects of two different toxic, aggregation prone proteins and accelerates their degradation. Parkin is also capable of binding both the molecular chaperone HSP70 and the proteasome, and is particularly suited to facilitate the degradation of aberrant misfolded proteins whose accumulation whose accumulation leads to aggregation, proteasomal inhibition and cytotoxicity. We propose that parkin appears to be the only known molecular with capacity to: 1) target aberrant proteins to the proteasome through polyubiquination. 2) assist in unfolding aberrant proteins through recruitment of molecular chaperones and 3) directly bind and present these aberrant proteins to the proteasome in a state suitable for entry and degradation. We will assess the validity of this model and determine the interaction of the molecular domains of parkin responsible for its overall function. To rapidly accomplish this goal, cell lines will be co-transfected with genes for toxic aberrant proteins Along with normal or specific mutant forms of parkin. Mutant forms of parkin will be assessed in this setting for their capacity to 1) reverse cytotoxicity 2) prevent protein aggregation 3) accelerate toxic protein degradation 4) maintain proteasomal function 5) bind HSP70 and the proteasome. After identifying the important molecular domains of parkin we will determine if their linkage within a single complex is essential for the overall function of the molecule. This enzyme may be particular importance to dopaminergic neurons where increased levels of oxidative injury to cellular proteins have been implicated in the pathogenesis of both inherited and sporadically occurring Parkinson's Disease. An enhanced understanding of the molecular basis for the neuroprotective properties of parkin could lead to the development of new therapeutics to present cellular injury and death in Parkinson's Disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZNS1-SRB-K (03))
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Murphy, Diane
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University of Maryland Baltimore
Schools of Medicine
United States
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Nivitchanyong, Toey; Tsai, Yien Che; Betenbaugh, Michael J et al. (2009) An improved in vitro and in vivo Sindbis virus expression system through host and virus engineering. Virus Res 141:1-12
Tsai, Yien Che; Fishman, Paul S; Thakor, Nitish V et al. (2003) Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J Biol Chem 278:22044-55