NDLI: A native interactor scaffolds and stabilizes toxic ATAXIN-1 oligomers in SCA1

Content Provider	PubMed Central
Author	Lasagna-reeves, Cristian A. Rousseaux, Maxime Wc Guerrero-muñoz, Marcos J. Park, Jeehye Jafar-nejad, Paymaan Richman, Ronald Lu, Nan Sengupta, Urmi Litvinchuk, Alexandra Orr, Harry T. Kayed, Rakez Zoghbi, Huda Y.
Editor	Strooper, Bart De
Copyright Year	2015
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.
Related Links	http://dx.doi.org/10.7554/elife.07558
Starting Page	7558
File Format	PDF
ISSN	2050084X
e-ISSN	2050084X
Journal	eLife
Volume Number	4
Language	English
Publisher	eLife Sciences Publications, Ltd
Publisher Date	2015-05-01
Access Restriction	Open
Rights Holder	eLife Sciences Publications, Ltd
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Microbiology Medicine Biochemistry, Genetics and Molecular Biology

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