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Study Implicates Potassium Channel Mutations in Neurodegeneration and Mental Retardation


For release: Sunday, February 26, 2006

For the first time, researchers have linked mutations in a gene that regulates how potassium enters cells to a neurodegenerative disease and to another disorder that causes mental retardation and coordination problems. The findings may lead to new ways of treating a broad range of disorders, including Alzheimer's and Parkinson's diseases. The study was funded in part by the National Institutes of Health's National Institute of Neurological Disorders and Stroke (NINDS).

"This type of gene has never before been linked to nerve cell death," says Stefan Pulst, M.D., of Cedars-Sinai Medical Center at the University of California, Los Angeles, who led the new study. The report will appear in the February 26, 2006, advance online publication of Nature Genetics.1

In the study, the researchers looked for the gene that caused a neurodegenerative movement disorder called spinocerebellar ataxia in a Filipino family. This disorder typically appears in adulthood and causes loss of neurons in the brain's cerebellum, resulting in progressive loss of coordination (ataxia). Dr. Pulst and his colleagues traced the disease in this family to mutations in a gene called KCNC3. The gene codes for one of the proteins that form potassium channels - pore-like openings in the cell membrane that control the flow of potassium ions into the cell. The researchers found a different KCNC3 mutation in a previously identified French family with a disease called spinocerebellar ataxia type 13, which causes childhood-onset ataxia, cerebellar degeneration, and mild mental retardation.

The KCNC3 gene codes for a type of potassium channel that normally opens and closes very quickly. This type of channel is particularly important in "fast-bursting neurons" that fire hundreds of times per second in the brain. "Fast-bursting neurons are like building blocks - they are used in the nervous system a lot," Dr. Pulst says. Among other places, these neurons are found in the brain's substantia nigra, where they aid in motor control, and in the hippocampus, where they play a role in learning. Previous studies have found abnormalities in the number of potassium channels in Parkinson's, Alzheimer's, and Huntington's diseases. Together with the new study, these findings suggest that potassium channel abnormalities may contribute to a wide variety of neurodegenerative diseases.

"This paper is a good example of how gene discovery is useful for giving clues about therapeutic targets and strategies, which is the most important goal of human gene discovery research in my view," says Katrina Gwinn-Hardy, M.D., the NINDS program director for Dr. Pulst's grant.

Through cell culture experiments, the researchers learned that the KCNC3 mutations in the Filipino and French families affect the potassium channel very differently. The mutation found in the Filipino family completely prevented the potassium channel from functioning. The mutation from the French family caused potassium channels to open earlier than normal and close too late. This reduced the rate at which the neurons could fire.

Researchers have long known that potassium channels are important for neuronal function. Mutations in other potassium channel genes have been linked to problems such as epilepsy, cardiac arrhythmias, and periodic muscle paralysis. One type of potassium channel defect has also been found in a disorder called episodic ataxia type 1 that causes brief episodes of ataxia without neurodegeneration. However, potassium channel mutations have never before been linked to neurodegenerative disease or mental retardation. The findings were surprising because mice lacking the KCNC3 gene have only mild behavioral changes, Dr. Pulst says.

It is not yet clear exactly how the potassium channel mutations cause neurodegeneration. One theory is that the mutations might increase the amount of calcium that can enter cells, causing them to die because of excitotoxicity (overstimulation). The altered potassium channels might prevent neurons from coping well with oxidative stress - damage from reactive molecules called free radicals that are produced during metabolism. The mutations also might cause subtle developmental defects that reduce the long-term survival of neurons, the researchers say.

The new findings suggest that spinocerebellar ataxia and other neurodegenerative diseases might be treatable with drugs that alter the activity of potassium channels. To maximize the benefits and reduce side effects, researchers would need to find drugs that are specific for this type of channel, Dr. Pulst says.

The investigators now plan to use cell cultures and animal models to help them learn exactly how the mutations cause neurodegeneration. These studies could lead to improved treatments for a number of diseases.

The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers. It is the lead Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

1Waters MF, Minassian NA, Stevanin G, Figueroa KP, Bannister JPA, Nolte D, Mock AF, Evidente VG, Fee D, Muller U, Durr A, Brice A, Papazian DM, Pulst SM. "Mutations iNature Geneticsn the voltage-gated potassium channel KCNC3 cause degenerative and developmental CNS phenotypes." , Advance Online Publication, February 26, 2006, doi: 10.1038/ng1758.

Last Modified August 7, 2009