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New Piece Added to Parkinson’s Puzzle
By Nancy Touchette

Three copies of the SNCA gene (labeled pink) occur on the mutant form of chromosome 4 (center) while the normal chromosome (top) contains one copy.

Researchers studying Parkinson's disease have found a large DNA repeat on chromosome 4 in a family affected by a severe form of the disease. The discovery provides new evidence that a protein called α-synuclein plays a key role in causing the disease.

Family members with the disease have a stretch of DNA containing nearly 2 million base pairs that is repeated three times. The repeated or “triplicated” region contains 17 predicted genes. One of these genes, SNCA , codes for the α-synuclein protein.

Mutations that change the sequence of α-synuclein have already been linked to Parkinson's. The protein is found in protein aggregates called Lewy bodies that frequently accumulate in the brains of patients with Parkinson's.

But the patients in the study do not have any mutations within the SNCA gene. Instead, they have extra copies of the gene.

“Of course, other genes could be involved but the fact that mutations in SNCA have already been found in Parkinson's patients suggests that this is the culprit,” says Andrew Singleton, of the National Institute on Aging in Bethesda, Maryland, the lead author of the study.

Singleton says that although the mutation is rare, it points to a role for the normal form of α-synuclein in contributing to Parkinson's disease. And it helps explain why some gene variants that influence the expression of the SNCA gene, but not the coding sequence, may increase the risk of developing the disease.

“Some of these mutations may be just nudging the level of protein up,” says Singleton. “This may be enough to trigger the disease in some situations.”

Two other genes have also been implicated in Parkinson's disease but it's not yet clear whether they act in concert to cause disease. Mutations in one gene called parkin codes for an enzyme that tags proteins for destruction.

Researchers are intent on finding whether mutations in parkin could lead to the accumulation of α-synuclein. Little is known about the normal function of α-synuclein or why having too much of it could cause disease.

“We're trying to connect the dots to figure out what is going on,” says Singleton. “This is another piece of the puzzle.”

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Singleton, A.B. et al. α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (October 2003).


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