Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1

Janghoo Lim, Juan Crespo-Barreto, Paymaan Jafar-Nejad, Aaron B. Bowman, Ronald Richman, David E. Hill, Harry T. Orr, Huda Y. Zoghbi

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267 Scopus citations


Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.

Original languageEnglish (US)
Pages (from-to)713-718
Number of pages6
Issue number7188
StatePublished - Apr 10 2008

Bibliographical note

Funding Information:
Acknowledgements We are grateful to M. Vidal for the human ORFeome and yeast two-hybrid screening technology; J. Valcárcel and W. Perry for anti-RBM17 antibody; H. Salz for dRBM17 mutant flies; Y. He for generating the RBM17 transgenic flies; H. Bellen and H. Jafar-Nejad, and members of the Zoghbi laboratory, for comments on the manuscript; and V. Brandt for editorial input. This research was supported by the NIH grants (H.Y.Z., H.T.O., M.V.), cores of the BCM-MRDDRC, the Ellison Foundation and the W.M. Keck Foundation awarded to M.V. and D.E.H., and Institute Sponsored Research from the DFCI Strategic Initiative in support of Center for Cancer Systems Biology. H.Y.Z. is an investigator with the Howard Hughes Medical Institute.


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