U. PENN (US)—Researchers have found evidence that mutations in a specific gene are a risk factor for Lou Gehrig’s disease, a condition also known as ALS or amyotrophic lateral sclerosis.

The study by researchers at the University of Pennsylvania shows that expansions of a run of the amino acid glutamine in the ataxin 2 gene are associated with an increased risk for ALS. The findings were published this week in Nature.

There is no cure for ALS and the current treatment only slows disease progression.

The identification of pathological interactions between the gene and another ALS-associated disease protein called TDP-43 should aid in the development of biomarkers and potentially new therapies.

The research team first identified genes that could suppress or enhance TDP-43 toxicity in yeast. Next, they transferred 5,500 yeast genes into a strain of yeast engineered to express human TDP-43. Among the genes that modified toxicity was the yeast counterpart of ataxin 2.

The researchers transferred the genes to fruit flies to assess effects of the genes and their interactions in the nervous system.

Results of the study were confirmed in fruit fly models, in biochemical analyses, and in human cells, revealing that ataxin 2 is a potent modifier of TDP-43. The study showed that the two interact in animal and cellular models to promote pathogenesis—linking the proteins and the disease.

“Because reducing ataxin 2 levels in yeast and flies was able to prevent some of the toxic effects of TDP-43, we think that this might be a novel therapeutic target for ALS,” says co-senior author Aaron Gitler, assistant professor of cell and developmental biology.

The ataxin 2 gene had previously been implicated in another neurodegenerative disease called spinocerebellar ataxia 2, or SCA2. Ataxin 2 contains a repeated stretch of the amino acid glutamine, abbreviated Q. This tract, called polyQ, is usually short, only about 22 or 23 Qs; however, if the polyQ tract expands to greater than 34 Qs, patients develop SCA2.

The new results show that intermediate-length polyQ repeats, between 27 and 33 Qs, longer than normal but shorter than what causes SCA2, increase the risk for developing ALS.

“There have been previous hints of similarities between ALS and SCA2,” says Michael Hart, a graduate student and co-first author of the study. “Our findings suggest a molecular explanation for these similarities and raise the possibility that treatments for one disease might be effective for the other.”

“Our findings do not mean that if you have 27Qs or more in your ataxin 2 gene that you will definitely get ALS, only that it increases risk for it,” Gitler adds.

Researchers from Penn, the Children’s Hospital of Philadelphia, and Goethe University contributed to the work, which was supported in part by the National Institutes of Health, the Pew Charitable Trusts, the National Institute of Neurological Disorders and Stroke, the National Institute of Aging, a Burroughs Wellcome Fund Career Award, the Deutsche Heredo-Ataxie Gesellschaft, the European Integrated Project on Spinocerebellar Ataxias, and the Deutsche Forschungsgemeinschaft.

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