title: A native interactor scaffolds and stabilizes toxic ATAXIN-1 oligomers in SCA1.
abstract: Recent studies indicate that soluble oligomers drive pathogenesis in several neurodegenerative proteinopathies, including Alzheimer and Parkinson disease. Curiously, the same conformational antibody recognizes different disease-related oligomers, despite the variations in clinical presentation and brain regions affected, suggesting that the oligomer structure might be responsible for toxicity. We investigated whether polyglutamine-expanded ATAXIN-1, the protein that underlies spinocerebellar ataxia type 1, forms toxic oligomers and, if so, what underlies their toxicity. We found that mutant ATXN1 does form oligomers and that oligomer levels correlate with disease progression in the Atxn1(154Q/+) mice. Moreover, oligomeric toxicity, stabilization and seeding require interaction with Capicua, which is expressed at greater ratios with respect to ATXN1 in the cerebellum than in less vulnerable brain regions. Thus, specific interactors, not merely oligomeric structure, drive pathogenesis and contribute to regional vulnerability. Identifying interactors that stabilize toxic oligomeric complexes could answer longstanding questions about the pathogenesis of other proteinopathies.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Lasagna-Reeves
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Maxime Wc
authors.initials: MW
authors.lastname: Rousseaux
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, United States.
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Guerrero-Muñoz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Jeehye
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Paymaan
authors.initials: P
authors.lastname: Jafar-Nejad
authors.affiliation: Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Richman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Lu
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, United States.
authors.forename: Urmi
authors.initials: U
authors.lastname: Sengupta
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Litvinchuk
authors.affiliation: Institute for Translational Neuroscience, University of Minnesota, Minnesota, United States.
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, United States.
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.affiliation: Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000067696:Ataxin-1 / Q000737:chemistry* / Q000633:toxicity*; D015153:Blotting, Western; D002531:Cerebellum / Q000378:metabolism*; D002850:Chromatography, Gel; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D010455:Peptides / Q000032:analysis; D012097:Repressor Proteins / Q000378:metabolism; D045442:Rotarod Performance Test; D020754:Spinocerebellar Ataxias / Q000378:metabolism* / Q000503:physiopathology*; D018675:Toxicity Tests
chemical_list: D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse; C498611:Cic protein, mouse; D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine
keywords: amyloid oligomers; ataxin-1; mouse; native interactors; neuroscience; proteinopathies