A native interactor scaffolds and stabilizes toxic ATAXIN-1 oligomers in SCA1
| Title: | A native interactor scaffolds and stabilizes toxic ATAXIN-1 oligomers in SCA1 |
|---|---|
| Authors: | 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 |
| Source: | eLife, Vol 4 (2015) |
| Publisher Information: | eLife Sciences Publications Ltd, 2015. |
| Publication Year: | 2015 |
| Collection: | LCC:Medicine LCC:Science LCC:Biology (General) |
| Subject Terms: | ataxin-1, amyloid oligomer, native interactor, proteinopathies, Medicine, Science, Biology (General), QH301-705.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2050-084X |
| Relation: | https://elifesciences.org/articles/07558; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.07558 |
| Access URL: | https://doaj.org/article/50bd66d718644c13ad6bb20b07f4c12d |
| Accession Number: | edsdoj.50bd66d718644c13ad6bb20b07f4c12d |
| Database: | Directory of Open Access Journals |
| ISSN: | 2050084X |
|---|---|
| DOI: | 10.7554/eLife.07558 |
| Published in: | eLife |
| Language: | English |