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 and Huda Y. Zoghbi ()
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Janghoo Lim: Department of Molecular and Human Genetics,
Juan Crespo-Barreto: Interdepartmental program in Cell and Molecular Biology,
Paymaan Jafar-Nejad: Department of Molecular and Human Genetics,
Aaron B. Bowman: Department of Molecular and Human Genetics,
Ronald Richman: Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA
David E. Hill: Harvard Medical School, Boston, Massachusetts 02115, USA
Harry T. Orr: Institute of Human Genetics, Biophysics and Molecular Biology, University of Minnesota, Minneapolis, Minnesota 55455, USA
Huda Y. Zoghbi: Department of Molecular and Human Genetics,

Nature, 2008, vol. 452, issue 7188, 713-718

Abstract: Abstract 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.

Date: 2008
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DOI: 10.1038/nature06731

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