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Us Team Identifies New Mutations Linked to Familial, Sporadic Parkinson s Disease

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A multi-center team of researchers has found that abnormal multiplication of the alpha-synuclein gene may increase the risk of developing familial and sporadic Parkinson’s disease, and may offer scientists with a new way of studying neurological conditions such as Alzheimer’s disease.

Several years ago, researchers identified mutations in the alpha synuclein gene in a few large families in whom the disease was “unusually common.” Since then, mutations in several other genes have also been linked to familial forms of Parkinson’s disease.

In the new study, which appears in the Oct. 31 issue of Science, investigators from the National Institute on Aging’s Laboratory of Neurogenetics, the Mayo Clinic, the National Institute of Neurological Disorders and Stroke, the National Human Genome Research Institute, and Georgetown University Medical Center analyzed blood samples from another affected family — the “Iowa kindred” — in which “many relatives” developed Parkinson’s disease or related neurological diseases.

This family, which was followed by these scientists “for many years,” was a kind of medical mystery because genetic analyses of some family members “initially showed no alpha-synuclein mutation,” the group said. This led the researchers to suspect “an entirely different” mutation — PARK4.

Conducting additional analyses of the entire genomes from these family members, including chromosome 4, on which the alpha synuclein gene is located, the team found that people with the disease had four copies of the alpha-synuclein gene instead of the usual two copies — a multiplication that results in too much synuclein, the protein implicated in Parkinson’s symptoms.

“This study is an exciting step forward in our understanding of this disease,” Andrew Singleton of the NIA said in a statement this week. “It contributes to the growing body of evidence suggesting that genetic variations in alpha-synuclein contribute to Parkinson’s disease” and “suggests that … both mutated and normal alpha synuclein behave in a way that is quantitatively different from the way the protein functions in people without Parkinson’s disease.”

The team also suggests that the mechanism of disease in this study “is similar to that seen in” individuals with Down syndrome, in which patients manufacture an excess of the protein beta-amyloid — which, when accumulated, may lead to the development of a form of Alzheimer’s disease.

Parkinson’s disease is a progressive disorder of the central nervous system affecting over 1.5 million people in the United States, according to the American Parkinson Disease Association. The disease is usually treated with levodopa, which is considered the standard treatment. Once it reaches the brain, levodopa is converted to dopamine which replaces the same substance not present in sufficient amounts in Parkinson’s patients, the APDA said. Treatment with levodopa does not, however, prevent the progressive changes of the brain typical of Parkinson’s disease.

Clinically, the disease is characterized by a decrease in spontaneous movements, gait difficulty, postural instability, rigidity, and tremor. It is caused by the degeneration of the pigmented neurons in the Substantia Nigra, and causes decreased dopamine availability. Though the major symptoms of Parkinson’s were first described in 1817, the pathological and biochemical changes in the brain were identified in the 1960s.

— KL

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