|Study Implicates Potassium Channel Mutations in Neurodegeneration
and Mental Retardation
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.*
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. Pulstís 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 nationís primary supporter
of biomedical research on the brain and nervous system.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it 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.