Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27–33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43–ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a common adult-onset neurodegenerative disease for which there is no cure. ALS is mostly sporadic but approximately 10% of cases have a familial component, most commonly the SOD1 (superoxide dismutase) gene. Yet SOD1 mutations account for only about 2% of cases in total, so the search for further ALS risk factors continues. The protein TDP-43 is thought to play a role — as yet undetermined — in ALS pathogenesis, and Elden et al. show that ataxin-2, a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. Analysis of DNA from 915 individuals shows ATXN2 to be a relatively common ALS susceptibility gene, accounting for up to 4.7% of ALS cases. These findings point to the TDP-43/ataxin-2 interaction as a possible target for therapeutic intervention. The causes of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) are poorly understood, although the protein TDP-43 seems to be involved. These authors show that the polyglutamine-containing protein ataxin 2 interacts with TDP-43 and is a potent modifier of TDP-43 toxicity. Moreover, intermediate-length polyglutamine expansions in the ataxin 2 gene significantly associate with ALS. These data establish the ataxin 2 gene as a new and relatively common ALS disease susceptibility gene.