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


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.

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Figure 1: Pbp1 is a dose-sensitive modifier of TDP-43 toxicity in yeast.
Figure 2: Atx2 is a dose-sensitive modifier of TDP-43 toxicity in Drosophila.
Figure 3: ATXN2 and TDP-43 interact in a manner dependent on RNA.
Figure 4: ATXN2 localization is perturbed in ALS patient neurons.
Figure 5: Intermediate-length ATXN2 polyQ expansions linked to ALS.

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This work was supported in part by a Pilot grant from the University of Pennsylvania Institute on Aging (A.D.G.), an NIH Director’s New Innovator Award 1DP2OD004417-01 (A.D.G.), 1R01NS065317-01 (A.D.G.), P01 AG-09215 (N.M.B.), AG-10124 (J.Q.T., V.M.V.D.) and AG-17586, (V.M.-Y.L., V.M.V.D.). A.D.G. is a Pew Scholar in the Biomedical Sciences, supported by The Pew Charitable Trusts. A.S.C.-P. is supported by a Burroughs Wellcome Fund Career Award and NIH K08 AG-033101-01. N.M.B. is an Investigator of the Howard Hughes Medical Institute. U.R. has support from the Deutsche Heredo-Ataxie Gesellschaft (DHAG) and Autosomal Dominant Cerebellar Ataxia (ADCA) Vereniging Nederland, G.A. from the European Integrated Project on Spinocerebellar Ataxias (EuroSCA) and the Deutsche Forschungsgemeinschaft (DFG) (AU96/11-1). We acknowledge W. den Dunnen and E. Brunt for autopsy tissue and M. Babl for technical assistance. We thank J. Epstein, J. Shorter, A. Cashmore and members of the Gitler laboratory for comments on the manuscript and discussions. We are grateful for the dedication of the patients and their families and for their invaluable contributions to this research.

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Authors and Affiliations



N.M.B. and A.D.G. are co-senior authors. M.P.H., H.-J.K., A.S.C.-P., F.G., U.R., G.A., J.Q.T., V.M.-Y.L., V.M.V.D., N.M.B. and A.D.G. designed the experiments. A.C.E., H.-J.K., M.P.H., B.S.J., X.F., M.A., R.G., M.M.L., U.R. and A.D.G. performed the research. D.J. and P.J.G. provided the reagents. D.C. and V.M.V.D. collected the clinical data. A.S.C.-P., L.E. and L.M. assessed clinical characteristics. M.P.H., H.-J.K., A.S.C.-P., F.G., A.P., L.E., L.M., U.R., G.A., J.Q.T., V.M.-Y.L., V.M.V.D., N.M.B. and A.D.G. analysed and interpreted data. N.M.B. and A.D.G. wrote the paper with contributions from all authors.

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Correspondence to Nancy M. Bonini or Aaron D. Gitler.

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[Competing Interests: A.D.G. is an inventor on patents and patent applications that have been licensed to FoldRx.]

Supplementary information

Supplementary Information

This file contains Supplementary Data, a Supplementary Discussion, additional References and Supplementary Figures 1-11 with legends. (PDF 990 kb)

Supplementary Table 1

This file contains Ataxin-2 polyQ lengths for ALS patients and control individuals and ages for control individuals. (XLS 35 kb)

Supplementary Table 2

This file contains the demographic and clinical characteristics of ALS patients and control individuals. (XLS 22 kb)

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Elden, A., Kim, HJ., Hart, M. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010).

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