ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons

• Published in: Human molecular genetics Vol. 21; no. 22; pp. 4888 - 4903
• Main Authors: Joselin, Alvin P, Hewitt, Sarah J, Callaghan, Steve M, Kim, Raymond H, Chung, Young-Hwa, Mak, Tak W, Shen, Jie, Slack, Ruth S, Park, David S
• Format: Journal Article
• Language: English
• Published: England 15.11.2012
• Subjects: Animals; Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology; Cell Line; Fibroblasts - metabolism; Mice; Mice, Knockout; Mitochondria - drug effects; Mitochondria - metabolism; Neurons - drug effects; Neurons - metabolism; Oncogene Proteins - metabolism; Oxidative Stress; Peroxiredoxins; Protein Deglycase DJ-1; Protein Kinases - deficiency; Protein Kinases - genetics; Protein Transport; Reactive Oxygen Species - metabolism; Rotenone - pharmacology; Signal Transduction; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/dds325

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.