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How Mutant Gene May Cause Inherited Forms of Parkinson’s

By Cheryl Simon Silver

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Although the causes of most cases of Parkinson’s disease remain a mystery, researchers have identified mutations in four genes in individuals whose Parkinson’s is inherited. The inherited forms of Parkinson’s are relatively rare but may provide clues to the biological origins of the more common forms of the disease.

New research suggests that one of the mutated genes disrupts the process by which certain proteins are degraded in dopamine neurons. The result seems to be that the neurons die.

David Sulzer of Columbia University Medical Center in New York City and his colleagues at the Albert Einstein College of Medicine focused on the mutant human alpha-synuclein gene. The research, published in Science, was primarily done in cells derived from mice.

The researchers believe that mutant proteins produced by the mutant alpha-synuclein gene accumulate in neurons, thereby blocking the normal degradation of these and other proteins that normally occurs in dopamine neurons.

Sulzer likens the problem to a garbage truck that breaks down on its way to the dump and blocks the road. Its trash never makes it to the dump, and neither does the trash of any truck behind it.

The speculation that important biological pathways are “gummed up” does not prove that the accumulation of mutant alpha-synuclein proteins causes familial Parkinson’s disease. But it does suggest that interference with the normal process of protein degradation in neurons may cause the disease.

Nor do the researchers know if problems with the degradation of proteins play a role in the more common, non-inherited forms of Parkinson’s disease. Sulzer and his group are now exploring the possibility that the pathway disruption that occurs in inherited Parkinson's also plays a role in the more common form of the disease.

“Even though most people with Parkinson’s disease do not have these particular mutations, there could be other structural changes in the proteins that make them behave like the mutant ones,” Sulzer says.

Sulzer, D. et al. Impaired Degradation of Mutant α-synuclein by Chaperone-Mediated Autophagy. Science 305, 1292-1295 (August 27, 2004).

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