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Spinocerebellar Ataxia 2 Gene is a Risk Gene for ALS


For release: Friday, November 26, 2010

Intermediate-length expansions (27-33 repeats) in the ataxin-2 gene are associated with an increased risk of ALS. Figure courtesy of Elden et al., Nature, 26 August 2010, Supp info.

A recent study has revealed one of the strongest genetic risk factors yet for amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), a paralyzing and ultimately fatal disease that affects approximately 1 in 100,000 people.

ALS attacks muscle-controlling neurons in the spinal cord; as these cells degenerate, the body’s muscles become progressively weaker.  Most cases of ALS are sporadic, meaning that the trigger for neuronal death is unknown.  In these cases, experts suspect that a mixture of environmental and genetic factors is at play.  However, investigators have found only a few genes that affect the risk of getting ALS. 

The new findings link sporadic ALS to a stutter-like mutation in the ataxin-2 gene.  This same kind of mutation – with a longer stutter – is known to be the culprit in another rare neurological disease, spinocerebellar ataxia type 2 (SCA2).  SCA2 primarily attacks the cerebellum and other brain regions involved in coordination and balance, but a rare number of patients do experience ALS-like symptoms.

The stutter in the ataxin-2 gene is technically known as a trinucleotide repeat expansion.  Trinucleotide repeats are normal bits of genetic code made up of a single repeating three-letter phrase.  Trinucleotide repeat expansions occur when the repeats multiply beyond the normal range, and are responsible for such neurological diseases as SCA2 and Huntington’s disease. 

Normally, the ataxin-2 gene contains 22-23 trinucleotide repeats.  In people with SCA2, the gene has 34 or more repeats.  The new study found that sporadic ALS is associated with "intermediate-length" expansions in the gene, containing 27-33 repeats.

"Having an expansion in the ataxin-2 gene does not necessarily cause ALS, but it does increase the risk for it," said Aaron Gitler, Ph.D, a cell biologist at the University of Pennsylvania School of Medicine in Philadelphia.  Dr. Gitler co-led the study with Nancy Bonini, Ph.D., also a biologist at UPenn.  The study was published in Nature*, and was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

To find the new ALS gene, "we started with the biology of the disease," said Dr. Gitler.  There are only a few genes with a confirmed role in sporadic ALS.  One of these genes encodes the SOD1 protein, an enzyme that acts like a natural antioxidant.  Another encodes TDP-43, which is involved in processing RNA (the intermediary between DNA and protein).  There is evidence that both proteins accumulate within the nerve cells of people with sporadic ALS, and that this process is toxic.

The UPenn-based team designed their study to identify genes that interact with TDP-43.  Their work began with experiments on yeast cells and fruit flies, and culminated in human genetic studies.

"This study illustrates the power of an unbiased genetic screen in yeast and in flies," said Margaret Sutherland, Ph.D., a program director at NINDS.  “The use of this approach to identify modifiers of cellular toxicity has continued to generate new discoveries and potential therapeutic targets for neurodegenerative diseases.”

An accumulation of TDP-43 is as toxic to yeast and flies as it is to human cells.  So the researchers grew yeast that made copious amounts of TDP-43, and then individually tested more than 5,000 yeast genes for their ability to modify the toxicity of TDP-43.  The yeast version of ataxin-2 enhanced TDP-43’s toxicity and hastened yeast cell death.  Likewise, in fruit flies engineered to over-produce TDP-43, the fly version of ataxin-2 enhanced neurodegeneration.

These experiments encouraged the research team to scan for ataxin-2 mutations in people with ALS.  They measured the number of ataxin-2 repeats in 915 patients with sporadic ALS and 980 control subjects, and found that people with intermediate-length repeat expansions (27-33 repeats) were more than twice as likely to have ALS.  Among people who had 29-33 repeats, there were 24 ALS cases and only three controls.

The researchers also examined the distribution of ataxin-2 protein in postmortem spinal cord tissue from ALS patients, in collaboration with neuropathologists John Trojanowski, M.D., Ph.D., and Virginia Lee, Ph.D., both at UPenn.  The team found that ataxin-2 accumulates abnormally within ailing motor neurons.  Within laboratory-grown cells, repeat expansions within ataxin-2 changed the distribution of TDP-43 as well.

Prior research suggests that, like TDP-43, the ataxin-2 protein is involved in RNA processing.  The UPenn-based team found that TDP-43 and ataxin-2 interact physically, possibly with RNA as a bridge between them.  These data add to growing evidence that connects ALS to defects in RNA processing.  (See MicroRNA Triggers Protective Response in Mice with ALS.)

The team’s findings are likely to spur further research on SCA2.  The researchers have already begun to investigate how the interaction between ataxin-2 and TDP-43 plays into that disease.  They have found that TDP-43 has an abnormal distribution within spinal cord and brainstem tissue from SCA2 patients.

“We’re getting at the molecular pathways involved in these diseases, and we are hopeful that we’ll be able to identify targets for therapy,” Dr. Bonini said.

Additional funding for this research was provided by NIH’s National Institute on Aging grants to Drs. Bonini, Lee, and Trojanowski, an NIH Director’s New Innovator Award to Dr. Gitler, and a pilot grant from the University of Pennsylvania Institute on Aging.

- By Daniel Stimson, Ph.D.

*Elden AC et al.  “Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.” Nature, August 26, 2010, Vol. 466 (7310), pp. 1069-75.

Last Modified November 1, 2012