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Study Identifies Genetic Risk Factor for ALS

By R&D Editors | October 15, 2010

research-1.jpg

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A role for the polyQ protein ataxin 2 in ALS was identified using yeast, fruit flies, and human ALS motor neurons. (Source: University of Pennsylvania) 

A study led by researchers from the University of Pennsylvania has identified a new genetic risk factor for amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease.

Using yeast and fruit flies as models, and following up with human DNA screening, the team found evidence that mutations in the ataxin 2 gene were a genetic contributor to the disease. More specifically, the study shows that expansions of a run of the amino acid glutamine in ataxin 2 are associated with an increased risk for ALS, with a frequency of 4.7 percent of ALS cases examined. The findings were published in Nature.

The identification of pathological interactions between ataxin 2 and TDP-43, another ALS-associated disease protein, together with the strong genetic association of ataxin 2 intermediate-length polyQ expansions and ALS, should aid in the development of biomarkers and empower the development of new therapies.

The researchers identified genes that could suppress or enhance TDP-43 toxicity in yeast and transferred 5,500 yeast genes into a strain of yeast they had engineered to express human TDP-43. Among the genes that modified toxicity was the yeast counterpart of ataxin 2. The team then transferred the genes to the fruit fly 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 ataxin 2 and TDP-43 interact in animal and cellular models to promote pathogenesis.

The results indicated a link between the proteins and the disease. For example, when the researchers directed expression of TDP-43 to the eye of the fruit fly, a progressive, age-dependent degeneration began. When directed to the motor neurons, flies experienced a progressive loss of motility. The higher the levels of ataxin 2, the greater was the toxicity of TDP-43, resulting in more severe degeneration. The less the amount of ataxin 2, the less was the toxicity.

“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 Aaron Gitler, assistant professor of cell and developmental biology at Penn’s School of Medicine.

The researchers extended these findings to ask if ataxin 2 showed alterations indicative of an association with ALS. They found that ataxin 2 appeared altered in spinal cord neurons from ALS patients. Following this up with analysis of the type of mutation that is found in ataxin 2 in its other disease, spinocerebellar ataxia 2, or SCA2, a polyQ expansion, they showed a link between expanded ataxin 2 repeats and risk for ALS. The expansions associated with risk for ALS were shorter than those associated with SCA2 but longer than in controls.

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.

“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 said.

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