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.