26 February 2006

Alzheimer's and Parkinson's May be Linked to K Channel Gene Mutation

Potassium Channels are vital gateways in all body cells, and play a particular role in nerve cells for propagating action potentials, or nerve impulses. Now, researchers at the US NIH National Institute of Neurological Disorders and Stroke (NINDS), have linked mutations in potassium channel genes (KCNC3) to different types of spinocerebellar ataxias, cerebellar degeneration, and a form of mental retardation. The mutated KCNC3 genes are linked to nerve death in these disorders. In addition, abnormal potassium channels have been found in Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease--all severe progressively degenerative neuronal maladies.

"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.

....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.

Potassium channels in many nerve types must be very fast, and their timing of opening and closing has to be precise. Very subtle changes in the gene sequence could throw off the timing of the channels. The more overt the changes, the earlier in life the defects would exhibit themselves as poor neuronal functioning.

This type of defect strikes me as a candidate for gene therapy, more than traditional pharmacotherapy. Until ultra-selective means of introducing genes into particular cell types are perfected, good and definitive therapies for such mutational changes may be delayed. Nevertheless, it is important to catalog these defects and their manifestations, so that scientists in all the various therapeutic approaches can evaluate potential therapies. This is the grunt work that absolutely must be done to pave the way for the magnificent treatments that will in time appear smooth and effortless.

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