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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Cysteine
Parkinson Disease
Protein Isoforms
Post Translational Protein Processing
Crystallization
Cultured Cells
Oxidative Stress
Cell Death
Mutation
cysteine sulfinic acid

ASJC Scopus subject areas

  • General

Cite this

The Parkinson's disease DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. / Canet-Avilés, Rosa M.; Wilson, Mark A.; Miller, David W.; Ahmad, Rili; McLendon, Chris; Bandyopadhyay, Sourav; Baptista, Melisa J.; Ringe, Dagmar; Petsko, Gregory A.; Cookson, Mark R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 24, 15.06.2004, p. 9103-9108.

Research output: Contribution to journalArticle

Canet-Avilés, RM, Wilson, MA, Miller, DW, Ahmad, R, McLendon, C, Bandyopadhyay, S, Baptista, MJ, Ringe, D, Petsko, GA & Cookson, MR 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, vol. 101, no. 24, pp. 9103-9108. https://doi.org/10.1073/pnas.0402959101
Canet-Avilés, Rosa M. ; Wilson, Mark A. ; Miller, David W. ; Ahmad, Rili ; McLendon, Chris ; Bandyopadhyay, Sourav ; Baptista, Melisa J. ; Ringe, Dagmar ; Petsko, Gregory A. ; Cookson, Mark R. / The Parkinson's disease DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 24. pp. 9103-9108.
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