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Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress.

The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in alpha-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.

Pubmed ID: 15525661

Authors

  • Moore DJ
  • Zhang L
  • Troncoso J
  • Lee MK
  • Hattori N
  • Mizuno Y
  • Dawson TM
  • Dawson VL

Journal

Human molecular genetics

Publication Data

January 1, 2005

Associated Grants

  • Agency: NIA NIH HHS, Id: AG05146
  • Agency: NINDS NIH HHS, Id: NS38377
  • Agency: NINDS NIH HHS, Id: NS43691

Mesh Terms

  • Cell Line, Tumor
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mitochondria
  • Mutation
  • Oncogene Proteins
  • Oxidative Stress
  • Parkinson Disease
  • Protein Binding
  • Ubiquitin-Protein Ligases