Poly-glutamine expansion in Ataxin-2 are genetic risk factor for ALS. Ataxin-2 with 22 glutamines is normal, while 27–33Qs impart ALS risk and if present with >34Qs, it is involved in spinocerebellar ataxia type 2 (SCA2). Ataxin-2 and TDP-43 physically interact in an RNA-dependent manner. Poly-glutamine expansions in ataxin-2 that have been identified in ALS enhance its stability and increase the TDP-43's cleavage and phosphorylation. Here, TARDBP is linked to amyotrophic lateral sclerosis.