A native interactor scaffolds and stabilizes toxic ATAXIN-1 oligomers in SCA1
Cristian A Lasagna-Reeves,
Maxime WC Rousseaux,
Marcos J Guerrero-Muñoz,
Jeehye Park,
Paymaan Jafar-Nejad,
Ronald Richman,
Nan Lu,
Urmi Sengupta,
Alexandra Litvinchuk,
Harry T Orr,
Rakez Kayed,
Huda Y Zoghbi
Affiliations
Cristian A Lasagna-Reeves
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Maxime WC Rousseaux
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Marcos J Guerrero-Muñoz
Department of Neurology, University of Texas Medical Branch, Galveston, United States
Jeehye Park
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Paymaan Jafar-Nejad
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Ronald Richman
Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Nan Lu
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Urmi Sengupta
Department of Neurology, University of Texas Medical Branch, Galveston, United States
Alexandra Litvinchuk
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Harry T Orr
Institute for Translational Neuroscience, University of Minnesota, Minnesota, United States
Rakez Kayed
Department of Neurology, University of Texas Medical Branch, Galveston, United States
Huda Y Zoghbi
Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
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 Atxn1154Q/+ 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.