In a paper published online in Nature Genetics Feb. 26, 2006, researchers reported on two mutations in one potassium channel that can cause two forms of ataxia. The more severe mutation, which led to early onset disease, also caused mild mental retardation.
There are known mutations of calcium channels that can cause neurodegeneration, but the mechanism there is brute force - excess calcium is highly toxic to cells. In contrast, senior author Stefan Pulst, director of the division of neurology at the Cedars-Sinai Medical Center, told BioWorld Today that alterations in potassium channel lead to more subtle changes in firing.
"We really associate them more with shaping the action potential," he said.
Indeed, a knockout mouse that lacks the channel in question altogether has few symptoms of any kind, leading Pulst to remark that "human beings might be the ultimate mouse models - you may have to live long enough to accumulate subtle changes" to see the damage that those subtle changes in the action potential cause.
Despite the less-than-encouraging data from the knockout mouse, the scientists decided to focus on the channel in question because it is expressed in neurons of the cerebellum, a part of the brain that controls motion.
Ataxia is a common name for a number of movement disorders that have difference causes; ataxia occurs when brain areas that control movement - most often the cerebellum - are damaged. Many ataxias are inherited, though they also can result from other disorders including stroke, multiple sclerosis, alcoholism and even vitamin deficiencies.
The work builds on previous research on a Filipino family with a heritable form of ataxia, in which the researchers had identified a region on chromosome 19 that showed mutations in affected members. That region partly overlapped with an area mutated in members of a French family with a more serious form of ataxia. Neither unaffected members of the same families nor control subjects without ataxia from the general population showed the mutations.
More detailed analysis found that the region contained a potassium channel, and that the channel was mutated in both cases in a way that changes its function. One mutation, in subunit four of the six-subunit channel, led to a nonfunctional channel; the other mutation, in subunit five, led to the channel's opening more easily and closing much more slowly than regular potassium channels of the same type; that is, the more serious mutation that was identified in the French family.
The idea that a completely nonfunctional channel is better to have than one that mostly works is counterintuitive, but Pulst explained that "the reason that a non-functional channel may be better is that there are other similar channels that may in part take over in shaping the action potential. It may be more difficult to compensate for the 'hyperactive' channel. For example, the single mouse knockout is virtually without symptoms; only when you knock out [a] related channel" - for a double knockout - "is the mouse sick."
Research into the causes of neurodegeneration had focused mainly on misfolded proteins, with identified culprits including prion proteins in Creutzfeldt-Jacob's disease, polyglutamine expansions in a number of diseases including Huntington's, and misfolded amyloid proteins in Alzheimer's.
Pulst said that though misfolded proteins clearly play a major role in neurodegeneration, the new data suggest channel mutations also could play a role. To wit, the potassium channel that Pulst and his colleagues studied is expressed not only in cerebellar neurons, it also is found in the substantia nigra, a major site of damage in Parkinson's disease, and the striatum, where Alzheimer's takes part of its toll.
While the exact mechanism by which the altered firing properties lead to disease still are unclear, possibilities include increased calcium influx during loner action potentials, as well as a reduced ability to cope with free radicals.
Pulst plans to investigate, by using a larger group of ataxia patients, how common the mutations his team identified are across the larger ataxia population. He hopes that his findings will, in the end, lead to the development of therapeutics for ataxias. Not better therapeutics, mind you - therapeutics.
"For Parkinson's, for example, we have a good number of drugs that make the patients better, at least symptomatically," he said. "We do not have anything like that for the ataxias."
The scientists work at the Cedars-Sinai Medical Center and the David Geffen School of Medicine at UCLA, both in Los Angeles; the H pital de la Salpetriere in Paris; Justus-Liebig-Universitaet in Giessen, Germany; the Mayo Clinic in Scottsdale, Ariz.; and the University of Kentucky College of Medicine in Lexington.