A study published in Nature (2010) reveals that intermediate-length polyglutamine (polyQ) expansions in the Ataxin-2 gene are associated with an increased risk of amyotrophic lateral sclerosis (ALS). The research shows that Ataxin-2, a polyQ protein linked to spinocerebellar ataxia type 2 (SCA2), acts as a potent modifier of TDP-43 toxicity in animal and cellular models. The proteins form a complex that depends on RNA, and both Ataxin-2 and TDP-43 show mislocalization in ALS and SCA2 patients. Analysis of the Ataxin-2 gene in 915 ALS patients revealed that intermediate-length polyQ expansions (27–33 Qs) are significantly associated with ALS, establishing ATXN2 as a common ALS susceptibility gene. These findings suggest that the TDP-43/Ataxin-2 interaction could be a promising therapeutic target for ALS and other TDP-43 proteinopathies. The study also highlights that Ataxin-2 is abnormally localized in spinal cord neurons of ALS patients, and that intermediate-length polyQ expansions in Ataxin-2 are significantly associated with ALS, with a frequency of 4.7% in cases unselected for family history. The research underscores the importance of RNA binding in the TDP-43/Ataxin-2 interaction and suggests that intermediate-length polyQ expansions in Ataxin-2 may be the most common genetic risk factor for ALS. The study also shows that Ataxin-2 polyQ expansions can enhance TDP-43 pathology and that Ataxin-2 and TDP-43 interact in a complex dependent on RNA. The findings provide new insights into the pathogenesis of ALS and highlight the potential for therapeutic intervention targeting the TDP-43/Ataxin-2 interaction.A study published in Nature (2010) reveals that intermediate-length polyglutamine (polyQ) expansions in the Ataxin-2 gene are associated with an increased risk of amyotrophic lateral sclerosis (ALS). The research shows that Ataxin-2, a polyQ protein linked to spinocerebellar ataxia type 2 (SCA2), acts as a potent modifier of TDP-43 toxicity in animal and cellular models. The proteins form a complex that depends on RNA, and both Ataxin-2 and TDP-43 show mislocalization in ALS and SCA2 patients. Analysis of the Ataxin-2 gene in 915 ALS patients revealed that intermediate-length polyQ expansions (27–33 Qs) are significantly associated with ALS, establishing ATXN2 as a common ALS susceptibility gene. These findings suggest that the TDP-43/Ataxin-2 interaction could be a promising therapeutic target for ALS and other TDP-43 proteinopathies. The study also highlights that Ataxin-2 is abnormally localized in spinal cord neurons of ALS patients, and that intermediate-length polyQ expansions in Ataxin-2 are significantly associated with ALS, with a frequency of 4.7% in cases unselected for family history. The research underscores the importance of RNA binding in the TDP-43/Ataxin-2 interaction and suggests that intermediate-length polyQ expansions in Ataxin-2 may be the most common genetic risk factor for ALS. The study also shows that Ataxin-2 polyQ expansions can enhance TDP-43 pathology and that Ataxin-2 and TDP-43 interact in a complex dependent on RNA. The findings provide new insights into the pathogenesis of ALS and highlight the potential for therapeutic intervention targeting the TDP-43/Ataxin-2 interaction.