Researchers find genetic duplication causes familial Parkinson's disease

Monday, September 27, 2004

JACKSONVILLE, Fla., Sept. 27, 2004 — A team of American and French researchers has discovered duplication of the alpha-synuclein gene causes Parkinson's disease in a French family. In affected individuals, age of onset, symptoms and symptom progression are similar to that observed in people with sporadic or unexplained cases of Parkinson's disease. The findings, reported in the Sept. 25 issue of Lancet, suggest a direct relationship between the amount of alpha-synuclein produced, the onset of Parkinson's disease, its severity and progression.

The research was led by Matthew Farrer, Ph.D. (Morris K. Udall Parkinson's Disease Research Center of Excellence at Mayo Clinic, Jacksonville, Fla.), Marie-Christine Chartier-Harlin, Ph.D., and Alain Destée, M.D. (Department of Neurology and INSERM, Lille, France).

Point mutations in the alpha-synuclein gene have previously been linked to the development of familial forms of Parkinson's disease. This led to the discovery that the encoded protein is a major component of Lewy bodies, the cellular inclusions in surviving brain cells. Lewy bodies are the key pathologic hallmark of sporadic Parkinson's disease and related disorders, including dementia with Lewy bodies, multiple system atrophy, and neurodegeneration with brain iron accumulation.

Last year, in two additional families, Farrer's group discovered that triplication of the alpha-synuclein gene results in a devastating form of Parkinson's. Afflicted members exhibit an earlier onset disease, which rapidly progresses, and they exhibit subsequent cognitive decline and dementia. "In contrast," Farrer says, "when our team of researchers looked at afflicted individuals in our French family who have an alpha-synuclein duplication, their disease onset was later, the progression of disease was slower and cognitive decline and dementia weren't prominent. The findings provide convincing evidence that the amount of alpha-synuclein expressed, or present, in the human brain influences the disease course."

Of note, Farrer's group and others have previously shown that common variation within the alpha-synuclein promoter sequence, an area of DNA upstream of the coding gene that is responsible for its expression, is associated with susceptibility to sporadic Parkinson's disease.

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