We have recently found in our preliminary studies that parkin, PINK1 and DJ-1 form a complex to promote 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. Our identification of, to our knowledge, the first human early onset recessive PD case with digenic inheritance of PINK1 and DJ-1 mutations, provides in vivo evidence of functional interaction of PINK1 and DJ-1. Moreover, overexpression of parkin in cells genetically ablated for either PINK1 or DJ-1 results in parkin accumulation, suggesting an essential role of the parkin/PINK1/DJ-1 complex in acute protein degradation. Furthermore, S-nitrosylation (transfer of the NO group to a critical cysteine thiol) of PD-related proteins can affect their function and subsequent protein misfolding 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 ubiquitinproteasomal pathways by mutations of parkin, PINK1 or DJ-1 contribute to a common pathogenic mechanism of PD, which warrants a further investigation. We hypothesize that parkin, PINK1 and DJ-1 form a functional E3 ligase complex to degrade unfolded/misfolded proteins induced by either oxidative stress or abnormal posttranslational modification. Disease-associated mutations should impair E3 ligase activity of the complex, resulting in increased susceptibility of stress-induced protein aggregation and neurodegeneration. In this proposed study, we will investigate regulation of formation and activity of the parkin/PINK1/DJ-1 complex by each complex component, and by nitrosative or oxidative stress. Moreover, we will determine the contribution of the parkin/PINK1/DJ-1 complex impairment to Lewy body-like aggregate formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES016738-05
Application #
8377575
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
$155,649
Indirect Cost
$69,953
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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