Spinocerebellar ataxia and other neurodegenerative diseases might be treatable w

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Spinocerebellar ataxia and other neurodegenerative diseases might be

treatable with drugs that alter the activity of potassium channels

http://www.news-medical.net/?id=16248

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 appears in 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.

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.

http://www.ninds.nih.gov