The study investigates the association between Ataxin-2 intermediate-length polyglutamine expansions and the risk of amyotrophic lateral sclerosis (ALS). Ataxin-2, a protein involved in RNA metabolism, is found to modify TDP-43 toxicity in animal and cellular models. The proteins form a complex that depends on RNA binding. Ataxin-2 is abnormally localized in spinal cord neurons of ALS patients, and TDP-43 shows mislocalization in spinocerebellar ataxia type 2 (SCA2). Analysis of the Ataxin-2 gene in 915 ALS patients revealed a significant association with intermediate-length polyQ tract expansions (4.7% of cases). These findings suggest that Ataxin-2 may be a new and potentially common ALS disease gene, and that the TDP-43/Ataxin-2 interaction could be a promising target for therapeutic intervention.The study investigates the association between Ataxin-2 intermediate-length polyglutamine expansions and the risk of amyotrophic lateral sclerosis (ALS). Ataxin-2, a protein involved in RNA metabolism, is found to modify TDP-43 toxicity in animal and cellular models. The proteins form a complex that depends on RNA binding. Ataxin-2 is abnormally localized in spinal cord neurons of ALS patients, and TDP-43 shows mislocalization in spinocerebellar ataxia type 2 (SCA2). Analysis of the Ataxin-2 gene in 915 ALS patients revealed a significant association with intermediate-length polyQ tract expansions (4.7% of cases). These findings suggest that Ataxin-2 may be a new and potentially common ALS disease gene, and that the TDP-43/Ataxin-2 interaction could be a promising target for therapeutic intervention.