Andrew C. Elden 1 , Hyung-Jun Kim 2 , Michael P. Hart 1 , Alice S. Chen-Plotkin 3 , 4 , Brian S. Johnson 1 , Xiaodong Fang 1 , Maria Armakola 1 , Felix Geser 3 , Robert Greene 3 , Min Min Lu 1 , Arun Padmanabhan 1 , Dana Clay 3 , Leo McCluskey 4 , Lauren Elman 4 , Denise Juhr 5 , Peter J. Gruber 5 , Udo Rüb 6 , Georg Auburger 7 , John Q. Trojanowski 3 , Virginia M.-Y. Lee 3 , Vivianna M. Van Deerlin 3 , Nancy M. Bonini 2 , Aaron D. Gitler 1
1 February 2011
Amyotrophic lateral sclerosis (ALS) is a devastating human neurodegenerative disease. The causes of ALS are poorly understood, although the protein TDP-43 has been suggested to play a critical role in disease pathogenesis. Here we show that Ataxin-2, a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2 (SCA2), is a potent modifier of TDP-43 toxicity in animal and cellular models. The proteins associate in a complex that depends on RNA. Ataxin-2 is abnormally localized in spinal cord neurons of ALS patients. Likewise, TDP-43 shows mislocalization in SCA2. To assess a role in ALS, we analyzed the Ataxin-2 gene ( ATXN2) in 915 ALS patients. We found intermediate-length polyQ expansions (27–33 Qs) in ATXN2 significantly associated with ALS. These data establish ATXN2 as a relatively common ALS disease susceptibility gene. Further, these findings indicate that the TDP-43/Ataxin-2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.