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

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 pI 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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 24 Pg. 9103-8 (Jun 15 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15181200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Neuroprotective Agents
• Neurotransmitter Agents
• Oncogene Proteins
• Protein Isoforms
• Recombinant Proteins
• PARK7 protein, human
• Protein Deglycase DJ-1
• Cysteine
• 1-Methyl-4-phenylpyridinium
• cysteine sulfinic acid

Topics

• 1-Methyl-4-phenylpyridinium (toxicity)
• Amino Acid Substitution
• Cell Line, Tumor
• Cysteine (analogs & derivatives, chemistry, genetics, metabolism)
• Humans
• Intracellular Membranes (metabolism)
• Intracellular Signaling Peptides and Proteins
• Mitochondria (metabolism)
• Models, Molecular
• Neuroprotective Agents (metabolism)
• Neurotransmitter Agents
• Oncogene Proteins (chemistry, genetics, metabolism)
• Oxidation-Reduction
• Oxidative Stress
• Protein Deglycase DJ-1
• Protein Isoforms
• Recombinant Proteins (chemistry, genetics, metabolism)
• Static Electricity
• Transfection