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Citation
Elden, A.C., Kim, H.J., Hart, M.P., Chen-Plotkin, A.S., Johnson, B.S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M.M., Padmanabhan, A., Clay-Falcone, D., McCluskey, L., Elman, L., Juhr, D., Gruber, P.J., Rub, U., Auburger, G., Trojanowski, J.Q., Lee, V.M., Van Deerlin, V.M., Bonini, N.M., Gitler, A.D. (2010). Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.  Nature 466(7310): 1069--1075.
FlyBase ID
FBrf0214156
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC2965417 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nature
    Title
    Nature
    Publication Year
    1869-
    ISBN/ISSN
    0028-0836
    Data From Reference
    Alleles (9)
    Genes (7)
    Human Disease Models (2)
    Natural transposons (1)
    Insertions (3)
    Experimental Tools (2)
    Transgenic Constructs (5)