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 α-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stres...

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Published in:Human molecular genetics 2005-01, Vol.14 (1), p.71-84
Main Authors: Moore, Darren J., Zhang, Li, Troncoso, Juan, Lee, Michael K., Hattori, Nobutaka, Mizuno, Yoshikuni, Dawson, Ted M., Dawson, Valina L.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cell Line, Tumor
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
Humans
Intracellular Signaling Peptides and Proteins
Mitochondria - genetics
Mitochondria - metabolism
Molecular and cellular biology
Mutation
Oncogene Proteins - genetics
Oncogene Proteins - metabolism
Oxidative Stress - genetics
Parkinson Disease - etiology
Parkinson Disease - genetics
Parkinson Disease - metabolism
Protein Binding - genetics
Protein Binding - physiology
Protein Deglycase DJ-1
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary: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 α-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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddi007