title: Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Janghoo
authors.initials: J
authors.lastname: Lim
authors.forename: Juan
authors.initials: J
authors.lastname: Crespo-Barreto
authors.forename: Paymaan
authors.initials: P
authors.lastname: Jafar-Nejad
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
authors.forename: Ronald
authors.initials: R
authors.lastname: Richman
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000483:Alleles; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D020798:Two-Hybrid System Techniques
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; C498610:CIC protein, human; C498611:Cic protein, mouse; D029721:Drosophila Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C121693:RBM17 protein, human; C528787:RBM17 protein, mouse; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D017413:Ribonucleoprotein, U2 Small Nuclear; C523271:SPF45 protein, Drosophila; C097188:polyglutamine