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

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. Polyglutamine diseases Spinocerebellar ataxia type 1 (SCA1) is an inherited neurodegenerative disease caused by faulty insertion of stretches of glutamines in the ataxin1 protein. Just how these 'polyglutamine expansions' make a protein neurotoxic — in SCA1 and eight other neurodegenerative diseases including Huntington's — is not clear. Lim et al . now show that the expanded polyglutamine tract can affect ataxin1 protein function in different ways, depending on the protein partners it associates with. Both loss of function and, more surprisingly, gain of function was observed. Spinocerebellar ataxia type 1 (SCA1) is an inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1. The expanded polyglutamine tract can affect the function of the ataxin1 protein in different ways, depending on the protein partners ataxin1 is associated with. This paper shows that polyglutamine expansion in one and the same protein can cause gain of function and loss of function toxicity at the same time.