We have recently found in our preliminary studies that parkin, PINK1 and DJ-1 form a complex topromote ubiquitination and degradation of the parkin substrates, parkin and synphilin-1.Pathogenic parkin and PINK1 mutants show impaired ability to degrade parkin and synphilin-1. Ouridentification of, to our knowledge, the first human early onset recessive PD case with digenicinheritance of PINK1 and DJ-1 mutations, provides in vivo evidence of functional interaction ofPINK1 and DJ-1. Moreover, overexpression of parkin in cells genetically ablated for either PINK1or DJ-1 results in parkin accumulation, suggesting an essential role of the parkin/PINK1/DJ-1complex in acute protein degradation. Furthermore, S-nitrosylation (transfer of the NO group to acritical cysteine thiol) of PD-related proteins can affect their function and subsequent proteinmisfolding and aggregation, as in the case of parkin, DJ-1 and protein-disulfide isomerase (PDI)(as studied in Project 3). Together, these findings indicate that impairments to ubiquitinproteasomalpathways by mutations of parkin, PINK1 or DJ-1 contribute to a common pathogenicmechanism of PD, which warrants a further investigation.We hypothesize that parkin, PINK1 and DJ-1 form a functional E3 ligase complex to degradeunfolded/misfolded proteins induced by either oxidative stress or abnormal posttranslationalmodification. Disease-associated mutations should impair E3 ligase activityof the complex, resulting in increased susceptibility of stress-induced protein aggregationand neurodegeneration. In this proposed study, we will investigate regulation of formation andactivity of the parkin/PINK1/DJ-1 complex by each complex component, and by nitrosative oroxidative stress. Moreover, we will determine the contribution of the parkin/PINK1/DJ-1 compleximpairment to Lewy body-like aggregate formation.
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