Expanded Ataxin 2 Genes a Major Contributor to ALS Risk

by Margaret Wahl on Wed, 2010-08-25 11:46

Small expansions in the ataxin 2 gene significantly increase the risk of developing of ALS

Expanded ataxin 2 genes lead to expanded ataxin 2 proteins, which seem to last too long in cells and apparently lead at least one other protein astray
Article Highlights:
  • When scientists studied DNA from 915 people with ALS and 980 without the disease, they found expanded ataxin 2 genes in 43 (4.7 percent) of those with ALS and only 14 (1.4 percent) of those without it.
  • They concluded that ataxin 2 expansions are significantly correlated with increased risk for developing ALS.
  • Expanded ataxin 2 protein molecules appear to have toxic interactions with TDP43, another protein implicated in ALS.
  • Blocking ataxin 2 interactions with TDP43 could become a new therapeutic avenue.

Scientists working in the United States and Germany have uncovered what appears to be the most common genetic contributor to amyotrophic lateral sclerosis so far identified.

The genetic factor is a segment of the ataxin 2 gene that's slightly longer than average, which causes the ataxin 2 protein to contain more molecules of the amino acid glutamine than it normally would.

This polyglutamine repeat expansion ("polyQ" expansion) then seems to cause the ataxin 2 protein to last longer than usual in cells and to interact in a toxic way with another protein, TDP43, which is already known to play a role in ALS.

The researchers say that the identification of toxic interactions between ataxin 2 and TDP43 protein molecules gives scientists a new target at which to aim experimental treatments.

The genetics of ALS

About 5 percent to 10 percent of the time, ALS is familial, meaning there's a family history of the disease. The other 90 percent to 95 percent of the time, it's sporadic, meaning there is no family history.

Mutations in genes for the SOD1 protein, the TDP43 protein, the FUS protein and others are known to cause ALS. There can be a history of ALS in families where one of these mutations is present, but sometimes a family history is lacking, even when an ALS-causing mutation is present in the person with ALS. (For instance, a parent who carried the genetic mutation may have died before ALS developed.)

It's commonly believed that most ALS cases are caused by a combination of genetic susceptibility factors and other as-yet-unidentified factors.

About the new findings

Nancy Bonini and Aaron Gitler, both at the University of Pennsylvania in Philadelphia, coordinated the study team, which published its findings Aug. 26, 2010, in the journal Nature.

The normal number of glutamine molecules in an ataxin 2 protein is typically 22 or 23. An expansion to more than 34 glutamines in this protein can cause a neurological disease known as spinocerebellar ataxia type 2 (SCA2).

After a series of laboratory observations, the researchers on the current study speculated that intermediate-range glutamine expansions — perhaps those between 24 and 34, which is longer than normal but shorter than the threshold for SCA2 — could be associated with the development of ALS.

They then studied DNA from 915 people with ALS, without regard to whether or not there was a family history of the disease, and 980 people with no neurologic disease.

Among those with ALS, 43 (4.7 percent) had ataxin 2 gene expansions that resulted in ataxin 2 protein molecules containing between 27 and 33 glutamines. Among those without ALS, only 14 (1.4 percent) had such expansions.

The difference means that these intermediate-length expansions "are significantly associated with increased risk for ALS," the researchers say.

The researchers then conducted experiments that showed that ataxin 2 protein molecules with longer-than-normal polyQ tracts have a longer life span in cells than ataxin 2 molecules with shorter polyQ tracts and that they interact with TDP43 protein molecules in a toxic way. (Recent experiments have also shown that TDP43 molecules, when abnormal, last longer than usual. See ALS-Causing TDP43 Overstays Its Welcome.)

Normally, TDP43 is found in the cell nucleus, and ataxin 2 is dispersed throughout the cytoplasm, the area of the cell outside the nucleus. However, in cells containing ataxin 2 with glutamine expansions, TDP43 was significantly more likely to be in the cytoplasm.

The researchers say they believe longer-than-normal ataxin 2 protein molecules may make TDP43 protein molecules more likely to move from the nucleus to the cytoplasm under stress conditions.

TDP43 protein that's outside the nucleus and in clumps has previously been shown to be a factor in ALS, whether or not there are mutations in the TDP43 gene.

Meaning for people with ALS

Interfering with the interaction between ataxin 2 and TDP43 could become a new therapeutic goal in ALS. Since the ataxin 2 expansion was found in nearly 5 percent of 915 patients who had ALS due to a variety of unspecified causes, this therapeutic avenue has the potential to be beneficial to a relatively large number of people with the disease.

For more information, see

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