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Study ties 'new' cell-death mechanism to developmental and degenerative brain disorders

An international research team has provided the first conclusive evidence that neurodevelopmental disorders such as mental retardation and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and ataxias can be caused, at least in part, by specific gene defects that interfere with the electrical impulses of rapid-firing brain nerve cells called bursting neurons.

The implicated gene, KCNC3, and two mutations are described in the journal Nature Genetics, published online Feb. 26, 2006. Until now, theories on degenerative cell death have centered on defective proteins and/or their accumulation and aggregation in the brain.

"The neurodegeneration field has been dominated by the hypothesis of misfolded proteins and their aggregation, but the identification of KCNC3 mutations and their functional characterization represent a novel avenue for understanding cell death," said Stefan M. Pulst, M.D., director of the Division of Neurology at Cedars-Sinai Medical Center, holder of the Carmen and Louis Warschaw Chair in Neurology, and principal investigator of this study.

KCNC3 forms a potassium channel, part of a biochemical mechanism that regulates the electrical impulses of bursting neurons. Although potassium channel mutations have previously been linked to episodic disorders such as seizures, this is the first time they have been identified as causative factors ?and potentially therapeutic targets ?in neurodegenerative diseases.

"Very recent neurophysiological studies of bursting neurons have led to speculation that voltage-gated potassium channels could be involved in human neurodegenerative disease, but proof has been lacking," Pulst said. "This is the first time neurodegeneration has been directly linked to potassium channel mutations."

In the Nature Genetics article, the researchers describe their analysis of two ataxia-causing mutations of the KCNC3 gene ?one present in a Filipino family and one in a French
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Source:Cedars-Sinai Medical Center


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