Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

Andrew C. Elden, Hyung-Jun Kim, Michael P. Hart, Alice S. Chen-Plotkin, Brian S. Johnson, Xiaodong Fang, Maria Armakola, Felix Geser, Robert Greene, Min Min Lu, Arun Padmanabhan, Dana Clay-Falcone, Leo McCluskey, Lauren Elman, Denise Juhr, Peter J. Gruber, Udo Rüb, Georg Auburger, John Q. Trojanowski, Virginia M.-Y. Lee, Vivianna M. Van Deerlin, Nancy M. Bonini () and Aaron D. Gitler ()
Additional contact information
Andrew C. Elden: University of Pennsylvania
Hyung-Jun Kim: Howard Hughes Medical Institute, University of Pennsylvania
Michael P. Hart: University of Pennsylvania
Alice S. Chen-Plotkin: University of Pennsylvania
Brian S. Johnson: University of Pennsylvania
Xiaodong Fang: University of Pennsylvania
Maria Armakola: University of Pennsylvania
Felix Geser: University of Pennsylvania
Robert Greene: University of Pennsylvania
Min Min Lu: University of Pennsylvania
Arun Padmanabhan: University of Pennsylvania
Dana Clay-Falcone: University of Pennsylvania
Leo McCluskey: University of Pennsylvania
Lauren Elman: University of Pennsylvania
Denise Juhr: The Children’s Hospital of Philadelphia
Peter J. Gruber: The Children’s Hospital of Philadelphia
Udo Rüb: Institute of Clinical Neuroanatomy, Dr Senckenberg Anatomy, Goethe University
Georg Auburger: Molecular Neurogenetics, Goethe University
John Q. Trojanowski: University of Pennsylvania
Virginia M.-Y. Lee: University of Pennsylvania
Vivianna M. Van Deerlin: University of Pennsylvania
Nancy M. Bonini: Howard Hughes Medical Institute, University of Pennsylvania
Aaron D. Gitler: University of Pennsylvania

Nature, 2010, vol. 466, issue 7310, 1069-1075

Abstract: Abstract 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 of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found 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.

Date: 2010
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DOI: 10.1038/nature09320

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