Mutations in the gene for the protein DJ-1 are known to cause early onset Parkinson’s disease (see ARF related news story). Exactly what DJ-1 does is unknown, however, so how the wild-type protein protects against the disease is unclear. Theories abound, some of the favorites suggesting that the protein is a protease, or that it protects against oxidative stress (see ARF related news story). Some new evidence supports the latter theory. In this week’s early online PNAS, Mark Cookson and colleagues at the National Institute on Aging, Bethesda, Maryland, and Brandeis University, Massachusetts, show that a redox switch prompts the movement of DJ-1, normally stationed in the cytosol, to the mitochondria.
DJ-1 has been shown to convert to a more acidic, negatively charged protein in response to oxidative stress, and some indications suggest that this is due to oxidation of a cysteine sulphydryl group to sulfinic acid. To put this theory to the test, first author Rosa Canet-Aviles and colleagues mutated each of the cysteines to alanine.
When these mutants were expressed in cells producing reactive oxygen species (ROS), only one of the proteins, with the mutation at amino acid 106, failed to convert to the more acidic form. The finding indicates that this particular cysteine may be the one that is oxidized to sulfinic acid. This is backed up by crystallographic evidence. The authors found that electron density maps of crystals of the wild-type protein were entirely consistent with a sulfinic group at cysteine 106.
What might be the physiological significance of this cysteine redox switch? To answer this, the authors compared the localization of wild-type and the C106A mutant. They found that unlike wild-type protein, the mutated protein did not localize to mitochondrial outer membranes in response to oxidative stress. This in turn may be related to the protein’s ability to protect cells against oxidative damage. When the authors exposed cells to MPTP, a chemical that damages mitochondria—and as a contaminant in synthetic heroin has caused Parkinsonism in drug abusers (see ARF related news story)—about 95 percent of wild-type cells survive, while only about 60 percent of cells expressing the C106A mutant do so.
Overall, the work suggests that DJ-1 responds to a redox switch and is then translocated to the outer membrane of the mitochondria. But many questions remain. How does oxidation of one cysteine to sulfinic acid cause translocation? And what does the protein do once it gets to the mitochondria?
Interestingly, a sulphydryl-to-sulfinic switch was just recently found in another class of proteins that is implicated in preventing oxidative stress. In the peroxiredoxins, a cysteine sulphydryl, which is part of the catalytic core, is converted to a sulfinic group, and this switch is accompanied by conversion of the protein from a low molecular weight redox enzyme, to a high molecular weight chaperone (see ARF recent related news story).
Lots of recent evidence points the finger squarely at reactive oxygen species as mediators of disease and a whole host of proteins as regulators of oxidative stress and potential attenuators of disease. The latter include DJ-1, peroxiredoxins, and pink1, a protein that causes Parkinsonism when mutated and which is located to the mitochondria (see ARF related news story), while wholesale disruption of mitochondrial transcription has been shown to cause late-onset neurodegeneration (see ARF related news story).—Tom Fagan
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- How to Turn a Peroxidase into a Chaperone—Just Add Stress
- Pink Mutations Link Parkinson’s Disease to Mitochondria
- Mitochondrial Gene Knockouts Lead to Late-Onset Neurodegeneration
No Available Further Reading
- Canet-Avilés RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, Baptista MJ, Ringe D, Petsko GA, Cookson MR. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9103-8. PubMed.