ALS, also known as Lou Gehrig’s disease, is a devastating adult onset neurodegenerative disease with no cure1
. In fact, we still know little about the causes. The disease is mostly sporadic (SALS) but approximately 10% of cases have a first or second-degree relative with ALS (familial ALS (FALS)). Mutations in SOD1
, encoding Cu/Zn superoxide dismutase, have been identified in ~20% of FALS cases2
, for an overall incidence of ~2%. Additional ALS disease genes have been identified that are even more rare. Identifying new and potentially common genetic risk factors for ALS will accelerate understanding of the disease, aid the development of biomarkers, and spur innovative new treatments.
Recently, the 43 kDa TAR DNA binding protein (TDP-43) was identified as a major player in sporadic and familial ALS. In 2006, TDP-43 was identified as the major disease protein in ubiquitinated cytoplasmic inclusions in neurons of patients with ALS and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP)3
. Subsequently, mutations in the gene encoding TDP-43 (TARDBP
) were found associated with familial cases of ALS and FTLD-TDP4,5
, arguing strongly for a central role of TDP-43 in disease pathogenesis. TDP-43 is normally a nuclear protein but pathological inclusions contain cytoplasmic TDP-43 aggregates, suggesting that altered subcellular localization of the protein may be critical to disease pathogenesis6
. Little is known about how loss of one or more of the biological functions of TDP-43, or how a potential toxic gain-of-function, might contribute to neurodegenerative disease. Moreover, nothing is known about genetic modifiers of TDP-43 pathogenesis or how other factors that interact with TDP-43 contribute to the risk of developing ALS or the age of disease onset.
In an unbiased screen to define modifiers of TDP-43 toxicity in yeast, we identified Ataxin-2 as a potent, dose-sensitive modulator of TDP-43 toxicity across multiple model systems. We show that the two proteins associate in a complex and are mislocalized in ALS patient spinal cord neurons. Given that Ataxin-2 is a polyQ disease gene, we analyzed the length of the polyQ repeat in over 900 sporadic and familial ALS patients. This revealed a significant association of Ataxin-2 intermediate-length polyQ tract expansions with ALS (4.7% of cases). We propose Ataxin-2 is a new and potentially common ALS disease gene. Further, these findings indicate that the TDP-43/Ataxin-2 interaction may be a promising target for therapeutic intervention.