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  • Title: ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons.
    Author: Joselin AP, Hewitt SJ, Callaghan SM, Kim RH, Chung YH, Mak TW, Shen J, Slack RS, Park DS.
    Journal: Hum Mol Genet; 2012 Nov 15; 21(22):4888-903. PubMed ID: 22872702.
    Abstract:
    Mutations in several genes, including Parkin, PTEN-induced kinase 1 (Pink1) and DJ-1, are associated with rare inherited forms of Parkinson's disease (PD). Despite recent attention on the function of these genes, the interplay between DJ-1, Pink1 and Parkin in PD pathogenesis remains unclear. In particular, whether these genes regulate mitochondrial control pathways in neurons is highly controversial. Here we report that Pink1-dependent Parkin translocation does occur in mouse cortical neurons in response to a variety of mitochondrial damaging agents. This translocation only occurs in the absence of antioxidants in the neuronal culturing medium, implicating a key role of reactive oxygen species (ROS) in this response. Consistent with these observations, ROS blockers also prevent Parkin recruitment in mouse embryonic fibroblasts. Loss of DJ-1, a gene linked to ROS management, results in increased stress-induced Parkin recruitment and increased mitophagy. Expression of wild-type DJ-1, but not a cysteine-106 mutant associated with defective ROS response, rescues this accelerated Parkin recruitment. Interestingly, DJ-1 levels increase at mitochondria following oxidative damage in both fibroblasts and neurons, and this process also depends on Parkin and possibly Pink1. These results not only highlight the presence of a Parkin/Pink1-mediated pathway of mitochondrial quality control (MQC) in neurons, they also delineate a complex reciprocal relationship between DJ-1 and the Pink1/Parkin pathway of MQC.
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