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; Aaron D. Gitler

doi:10.1038/nature09320

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. LeeVivianna M. Van Deerlin, Nancy M. Bonini, Aaron D. Gitler

Research output: Contribution to journal › Article › peer-review

1024 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1069-1075
Number of pages	7
Journal	Nature
Volume	466
Issue number	7310
DOIs	https://doi.org/10.1038/nature09320
State	Published - Aug 26 2010
Externally published	Yes

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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., Rüb, U., Auburger, G., Trojanowski, J. Q., ... Gitler, A. D. (2010). Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature, 466(7310), 1069-1075. https://doi.org/10.1038/nature09320

@article{02e6f6b55c35457695c33f0bbb392ac7,

title = "Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS",

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.",

author = "Elden, {Andrew C.} and Kim, {Hyung Jun} and Hart, {Michael P.} and Chen-Plotkin, {Alice S.} and Johnson, {Brian S.} and Xiaodong Fang and Maria Armakola and Felix Geser and Robert Greene and Lu, {Min Min} and Arun Padmanabhan and Dana Clay-Falcone and Leo McCluskey and Lauren Elman and Denise Juhr and Gruber, {Peter J.} and Udo R{\"u}b and Georg Auburger and Trojanowski, {John Q.} and Lee, {Virginia M.Y.} and {Van Deerlin}, {Vivianna M.} and Bonini, {Nancy M.} and Gitler, {Aaron D.}",

note = "Funding Information: Acknowledgements This work was supported in part by a Pilot grant from the University of Pennsylvania Institute on Aging (A.D.G.), an NIH Director{\textquoteright}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.",

year = "2010",

month = aug,

day = "26",

doi = "10.1038/nature09320",

language = "English (US)",

volume = "466",

pages = "1069--1075",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7310",

}

Elden, AC, Kim, HJ, Hart, MP, Chen-Plotkin, AS, Johnson, BS, Fang, X, Armakola, M, Geser, F, Greene, R, Lu, MM, Padmanabhan, A, Clay-Falcone, D, McCluskey, L, Elman, L, Juhr, D, Gruber, PJ, Rüb, U, Auburger, G, Trojanowski, JQ, Lee, VMY, Van Deerlin, VM, Bonini, NM & Gitler, AD 2010, 'Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS', Nature, vol. 466, no. 7310, pp. 1069-1075. https://doi.org/10.1038/nature09320

TY - JOUR

T1 - Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

AU - Elden, Andrew C.

AU - Kim, Hyung Jun

AU - Hart, Michael P.

AU - Chen-Plotkin, Alice S.

AU - Johnson, Brian S.

AU - Fang, Xiaodong

AU - Armakola, Maria

AU - Geser, Felix

AU - Greene, Robert

AU - Lu, Min Min

AU - Padmanabhan, Arun

AU - Clay-Falcone, Dana

AU - McCluskey, Leo

AU - Elman, Lauren

AU - Juhr, Denise

AU - Gruber, Peter J.

AU - Rüb, Udo

AU - Auburger, Georg

AU - Trojanowski, John Q.

AU - Lee, Virginia M.Y.

AU - Van Deerlin, Vivianna M.

AU - Bonini, Nancy M.

AU - Gitler, Aaron D.

N1 - Funding Information: Acknowledgements 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.

PY - 2010/8/26

Y1 - 2010/8/26

N2 - 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.

AB - 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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U2 - 10.1038/nature09320

DO - 10.1038/nature09320

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C2 - 20740007

AN - SCOPUS:77956155218

SN - 0028-0836

VL - 466

SP - 1069

EP - 1075

JO - Nature

JF - Nature

IS - 7310

ER -

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

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