In today's SciencExpress, researchers from Italy, France, and The Netherlands report that mutations in DJ-1, a protein of unknown function, can lead to Parkinson's disease.
Led by Vincenzo Bonifati and Peter Heutink at Erasmus Medical Center, Rotterdam, the investigators compared genetic maps of unrelated Dutch and Italian families affected by a rare, recessive form of Parkinsonism called PARK7. The maps helped narrow down the field of candidate genes to around 100. The researchers then examined these genes for mutations and found a large deletion of the DJ-1 gene, comprising exons 1 to 5, in the Dutch family.
Further analysis showed that the Italian families had a single-point mutation, resulting in the substitution of a proline for a leucine residue in the DJ-1 protein. The authors used molecular modeling algorithms to predict that this single mutation disrupts an alpha helix section of the protein that extends on either side of the leucine, which is itself conserved among several DJ-1 homologs in prokaryotes and bacteria.
Though the exact function of DJ-1 is not understood, it is known to be modified in response to oxidative stimuli like hydrogen peroxide, suggesting that it may be involved in an oxidative stress response. However, the authors note that DJ-1 has also been associated with RNA-binding proteins and PIAS proteins, which modulate the activity of various transcription factors by sumoylation. Whatever the role of DJ-1, its inactivation has profound effects on neurons, causing a cellular redistribution of the protein and ultimately leading to the neurodegeneration associated with Parkinson's.
"This is really fascinating and it raises several questions," commented Tim Greenamyre, professor of neurology at Emory University. "First, how does a single amino acid substitution end up targeting the mutant protein to mitochondria? Does the proline residue lead to a conformational change that simulates a mitochondrial targeting sequence? Does the putative normal function of this protein in the oxidative stress response have anything to do with its role in pathogenesis?
"Certainly, this finding places mitochondria and oxidative stress at center stage in the pathogenesis of both genetic and environmental forms of PD," he added.—Tom Fagan
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- Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003 Jan 10;299(5604):256-9. Epub 2002 Nov 21 PubMed.