The Parkinson's disease DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization

Rosa M. Canet-Avilés, Mark A. Wilson, David W. Miller, Rili Ahmad, Chris McLendon, Sourav Bandyopadhyay, Melisa J. Baptista, Dagmar Ringe, Gregory A. Petsko, Mark R. Cookson

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Abstract

Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, leading to the suggestion that DJ-1 is protective under these conditions. We addressed whether this represents a posttranslational modification at cysteine residues by systematically mutating cysteine residues in human DJ-1. WT or C53A DJ-1 was readily oxidized in cultured cells, generating a pl 5.8 isoform, but an artificial C106A mutant was not. We observed a cysteine-sulfinic acid at C106 in crystalline DJ-1 but no modification of C53 or C46. Oxidation of DJ-1 was promoted by the crystallization procedure. In addition, oxidation-induced mitochondrial relocalization of DJ-1 and protection against cell death were abrogated in C106A but not C53A or C46A. We suggest that DJ-1 protects against neuronal death, and that this is signaled by acidification of the key cysteine residue, C106.

Original languageEnglish (US)
Pages (from-to)9103-9108
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number24
DOIs
StatePublished - Jun 15 2004

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Canet-Avilés, R. M., Wilson, M. A., Miller, D. W., Ahmad, R., McLendon, C., Bandyopadhyay, S., Baptista, M. J., Ringe, D., Petsko, G. A., & Cookson, M. R. (2004). The Parkinson's disease DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proceedings of the National Academy of Sciences of the United States of America, 101(24), 9103-9108. https://doi.org/10.1073/pnas.0402959101