title: Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes.
abstract: Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine tract in ataxin-1 (ATXN1). SCA1 pathogenesis studies support a model in which the expanded glutamine tract causes toxicity by modulating the normal activities of ATXN1. To explore native interactions that modify the toxicity of ATXN1, we generated a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a highly conserved paralog of SCA1, and tested the role of this protein in SCA1 pathology. Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, we found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC). Our results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and they underscore the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
authors.forename: Yung C
authors.initials: YC
authors.lastname: Lam
authors.forename: Paymaan
authors.initials: P
authors.lastname: Jafar-Nejad
authors.forename: Hung-Kai
authors.initials: HK
authors.lastname: Chen
authors.forename: Ronald
authors.initials: R
authors.lastname: Richman
authors.forename: Rodney C
authors.initials: RC
authors.lastname: Samaco
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.forename: Juliette J
authors.initials: JJ
authors.lastname: Kahle
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D042622:DNA Repeat Expansion; D053595:Embryonic Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000032:analysis; D011689:Purkinje Cells / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; C504975:Atxn1l protein, mouse; C498611:Cic protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine