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

  1. Cristian A Lasagna-Reeves
  2. Maxime W C Rousseaux
  3. Marcos J Guerrero-Munoz
  4. Jeehye Park
  5. Paymaan Jafar-Nejad
  6. Ronald Richman
  7. Nan Lu
  8. Urmi Sengupta
  9. Alexandra Litvinchuk
  10. Harry T Orr
  11. Rakez Kayed
  12. Huda Y Zoghbi  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. University of Texas Medical Branch, United States
  3. Howard Hughes Medical Institute, Baylor College of Medicine, United States
  4. University of 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 Ataxin1, 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.

Article and author information

Author details

  1. Cristian A Lasagna-Reeves

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  2. Maxime W C Rousseaux

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  3. Marcos J Guerrero-Munoz

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    Competing interests
    No competing interests declared.
  4. Jeehye Park

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  5. Paymaan Jafar-Nejad

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  6. Ronald Richman

    Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  7. Nan Lu

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  8. Urmi Sengupta

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    Competing interests
    No competing interests declared.
  9. Alexandra Litvinchuk

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  10. Harry T Orr

    Institute for Translational Neuroscience, University of Minnesota, Minnesota, United States
    Competing interests
    No competing interests declared.
  11. Rakez Kayed

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    Competing interests
    No competing interests declared.
  12. Huda Y Zoghbi

    Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
    For correspondence
    hzoghbi@bcm.edu
    Competing interests
    Huda Y Zoghbi, Senior editor, eLife.

Reviewing Editor

  1. Bart De Strooper, VIB Center for the Biology of Disease, KU Leuven, Belgium

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#AN-1013) of Baylor College of Medicine

Version history

  1. Received: March 18, 2015
  2. Accepted: May 18, 2015
  3. Accepted Manuscript published: May 19, 2015 (version 1)
  4. Version of Record published: June 11, 2015 (version 2)

Copyright

© 2015, Lasagna-Reeves et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Cristian A Lasagna-Reeves
  2. Maxime W C Rousseaux
  3. Marcos J Guerrero-Munoz
  4. Jeehye Park
  5. Paymaan Jafar-Nejad
  6. Ronald Richman
  7. Nan Lu
  8. Urmi Sengupta
  9. Alexandra Litvinchuk
  10. Harry T Orr
  11. Rakez Kayed
  12. Huda Y Zoghbi
(2015)
A native interactor scaffolds and stabilizes toxic Ataxin-1 oligomers in SCA1
eLife 4:e07558.
https://doi.org/10.7554/eLife.07558

Share this article

https://doi.org/10.7554/eLife.07558

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