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Elife. 2015 May 19;4. doi: 10.7554/eLife.07558.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
2
Department of Neurology, University of Texas Medical Branch, Galveston, United States.
3
Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
4
Institute for Translational Neuroscience, University of Minnesota, Minnesota, United States.

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.

KEYWORDS:

amyloid oligomers; ataxin-1; mouse; native interactors; neuroscience; proteinopathies

PMID:
25988806
PMCID:
PMC4462648
DOI:
10.7554/eLife.07558
[Indexed for MEDLINE]
Free PMC Article

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