Project 1: The Parkin/PINK1/DJ-1 E3 Ligase Complex and Degradation of Misfolded

Information

  • Research Project
  • 8292286
  • ApplicationId
    8292286
  • Core Project Number
    P01ES016738
  • Full Project Number
    5P01ES016738-04
  • Serial Number
    16738
  • FOA Number
  • Sub Project Id
    1
  • Project Start Date
    7/1/2011 - 12 years ago
  • Project End Date
    6/30/2013 - 10 years ago
  • Program Officer Name
  • Budget Start Date
    7/1/2011 - 12 years ago
  • Budget End Date
    6/30/2012 - 11 years ago
  • Fiscal Year
    2011
  • Support Year
    4
  • Suffix
  • Award Notice Date
    9/29/2011 - 12 years ago

Project 1: The Parkin/PINK1/DJ-1 E3 Ligase Complex and Degradation of Misfolded

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.

IC Name
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
  • Activity
    P01
  • Administering IC
    ES
  • Application Type
    5
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
  • Sub Project Total Cost
    140158
  • ARRA Funded
    False
  • CFDA Code
  • Ed Inst. Type
  • Funding ICs
    NIEHS:140158\
  • Funding Mechanism
    Research Projects
  • Study Section
    ZES1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    SANFORD-BURNHAM MEDICAL RESEARCH INSTIT
  • Organization Department
  • Organization DUNS
    020520466
  • Organization City
    LA JOLLA
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    920371005
  • Organization District
    UNITED STATES