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Discovery of Gene for a Rare Form of Ataxia Could Help Understand ALS

Not all Packard Center research deals directly with amyotrophic lateral sclerosis (ALS). The reason behind that is sound: other neurological diseases with similar symptoms or key bits of biology in common can shed extra light on Lou Gehrig’s disease.

So the recent announcement that scientists found the gene for spinocerebellar ataxia type 5 (SCA5) is certainly a source of hope for patients with that inherited neurological disorder. “But it’s also a plus for ALS research,” says Packard Center Director Jeffrey Rothstein, “because it likely means better understanding of at least two pivotal areas that go wrong in ALS patients’ neurons.”

A decade ago, Rothstein uncovered a cell protein, called beta-3 spectrin, that acts like a tether for certain protective molecules, moving them, then holding them at the right place in nerve cell membranes. The tethered molecules — glutamate transporters — are important because they normally clear nerve cell synapses of excess nerve transmitter. Specifically, they sop up the nerve transmitter glutamate and prevent harmful over-stimulation. That overstimulation, or excitotoxicity, kills nerve cells both in SCA5 and in ALS, though some of the particulars differ.

In ALS, excitotoxicity most affects spinal motor neurons. In SCA5, it’s specifically the cerebellum’s Purkinje cells. Over several decades, patients with SCA5 gradually lose cerebellar function, namely, they lose coordination and muscle control as Purkinje neurons disappear.

In this latest research, reported in the journal, Nature Genetics, a team of scientists that included Rothstein, at Johns Hopkins, and that was headed by Laura Ranum at the University of Minnesota, tied cell death in SCA5 to a tether that doesn’t tether. Basically, mutations from two of the three families studied lead to flaws in beta-3 spectrin — the tether — and most likely keep the molecule from properly positioning glutamate transporters in Purkinje cells. As you’d expect, the scientists recovered fewer glutamate transporters from patients’ cell membranes than from healthy ones.

In ALS, Rothstein discovered a decade ago, patients also have fewer glutamate transporters, in this case on their motor neurons, but not for the same reason. “Still, in both diseases, the effect is to increase excitotoxicity and harm cells,” he says.

The new study is also important because it highlights a second problem area common to SCA5 and ALS, that of cell transport. Spectrin has other roles in nerve cells besides tethering. And the beta-3 spectrin mutation found in one of the study’s SCA5 families apparently upsets the molecule’s normal role in helping move necessary materials throughout nerve cells. Specifically, the mutation disrupts spectrin’s interaction with a molecular “motor” that shuttles proteins through the cell.

Recent work by Packard scientists and others has shown that cell transport, and “motor” activity in ALS animal models and in patients is also abnormal, though not because of a mutation in the beta-3 spectrin gene.

“The results of our work and that of other researchers,” Rothstein concludes, “suggest that even though different beta-3 spectrin mutations disrupt different cell processes, they all eventually bring about death of a particular brain cell and the symptoms of SCA5.” The studies that follow, he says, should help understand more specifically how things go awry downstream from the initial flaws, where SCA5 and ALS have common chemical paths.

In an interesting twist, the Minnesota members of the research team discovered that an 11-generation family descended from the grandparents of Abraham Lincoln has the beta-3 spectrin mutation. President Lincoln, they say, had a 25% risk of having the gene and may himself have had SCA5.

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