¹Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ²Department of Biology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ³Department of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ⁴Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ⁵The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. ⁶Institute of Clinical Neuroanatomy, Dr Senckenberg Anatomy, Goethe University, Frankfurt am Main D-60590, Germany. ⁷Molecular Neurogenetics, Department of Neurology, Goethe University, Frankfurt am Main D-60528, Germany

^*These authors contributed equally to this work.
Correspondence to: Aaron D. Gitler or Nancy M. Bonini

The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement ofATXN2inALS,weanalysed the length of the polyQrepeat in theATXN2 gene in 915ALSpatients.Wefound that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43–ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.