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Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation.

Mutations in PARKIN, pten-induced putative kinase 1 (PINK1), and DJ-1 are individually linked to autosomal recessive early-onset familial forms of Parkinson disease (PD). Although mutations in these genes lead to the same disease state, the functional relationships between them and how their respective disease-associated mutations cause PD are largely unknown. Here, we show that Parkin, PINK1, and DJ-1 formed a complex (termed PPD complex) to promote ubiquitination and degradation of Parkin substrates, including Parkin itself and Synphilin-1 in neuroblastoma cells and human brain lysates. Genetic ablation of either Pink1 or Dj-1 resulted in reduced ubiquitination of endogenous Parkin as well as decreased degradation and increased accumulation of aberrantly expressed Parkin substrates. Expression of PINK1 enhanced Parkin-mediated degradation of heat shock-induced misfolded protein. In contrast, PD-pathogenic Parkin and PINK1 mutations showed reduced ability to promote degradation of Parkin substrates. This study identified a functional ubiquitin E3 ligase complex consisting of PD-associated Parkin, PINK1, and DJ-1 to promote degradation of un-/misfolded proteins and suggests that their PD-pathogenic mutations impair E3 ligase activity of the complex, which may constitute a mechanism underlying PD pathogenesis.

Pubmed ID: 19229105

Authors

  • Xiong H
  • Wang D
  • Chen L
  • Choo YS
  • Ma H
  • Tang C
  • Xia K
  • Jiang W
  • Ronai Z
  • Zhuang X
  • Zhang Z

Journal

The Journal of clinical investigation

Publication Data

March 2, 2009

Associated Grants

  • Agency: NIEHS NIH HHS, Id: P01 ES 016738
  • Agency: NIDCD NIH HHS, Id: R01 DC 006497
  • Agency: NINDS NIH HHS, Id: R01 NS 057289

Mesh Terms

  • Cell Line, Tumor
  • Cytosol
  • Gene Deletion
  • Genes, Recessive
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mitochondria
  • Neuroblastoma
  • Oncogene Proteins
  • Parkinson Disease
  • Protein Denaturation
  • RNA, Messenger
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • alpha-Synuclein