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Study Identifies New Genetic Risk Factor for Lou Gehrig's Disease

August 26, 2010

An international study led by biologists and neuroscientists from the University of Pennsylvania, published this week in Nature, has identified a new genetic risk factor for amyotrophic lateral sclerosis, which is commonly known as ALS or Lou Gehrig’s disease.

Using yeast and fruit fly as simple, yet rapid and powerful models, and then 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 identification of pathological interactions between ataxin 2 and TDP-43, another ALS-associated disease protein should aid in the development of biomarkers and empower the development of new therapies for this disease.  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 in a manner to promote pathogenesis.

“This is a very exciting study using a novel approach to identify risk factors in ALS,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D.  “The association between TDP-43 and ataxin 2 is intriguing and further studies will hopefully shed more light on how these interactions are linked to ALS.”

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 the toxicity of TDP-43, resulting in more severe degeneration and the less the amount of ataxin 2, the less 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,” said study co-senior author Aaron Gitler, Ph.D., assistant professor of Cell and Developmental Biology at Penn’s School of Medicine.

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 a person’s risk for developing ALS.

“Our findings do not mean that if you have 27 Qs or more in your ataxin 2 gene that you will definitely get ALS, only that it increases risk for it,” Gitler added.  “However, the identification of a novel and potentially common ALS disease gene from a simple yeast screen, leveraged by the more complex model created in fruit flies, underscores the extraordinary power of yeast and fly as model systems for gaining insight into human disease pathogenesis.”

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