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.

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

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.

Metrics

  • 2,409
    views
  • 736
    downloads
  • 29
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Neuroscience
    Yisi Liu, Pu Wang ... Hongwei Zhou
    Short Report

    The increasing use of tissue clearing techniques underscores the urgent need for cost-effective and simplified deep imaging methods. While traditional inverted confocal microscopes excel in high-resolution imaging of tissue sections and cultured cells, they face limitations in deep imaging of cleared tissues due to refractive index mismatches between the immersion media of objectives and sample container. To overcome these challenges, the RIM-Deep was developed to significantly improve deep imaging capabilities without compromising the normal function of the confocal microscope. This system facilitates deep immunofluorescence imaging of the prefrontal cortex in cleared macaque tissue, extending imaging depth from 2 mm to 5 mm. Applied to an intact and cleared Thy1-EGFP mouse brain, the system allowed for clear axonal visualization at high imaging depth. Moreover, this advancement enables large-scale, deep 3D imaging of intact tissues. In principle, this concept can be extended to any imaging modality, including existing inverted wide-field, confocal, and two-photon microscopy. This would significantly upgrade traditional laboratory configurations and facilitate the study of connectomes in the brain and other tissues.

    1. Neuroscience
    2. Physics of Living Systems
    Moritz Schloetter, Georg U Maret, Christoph J Kleineidam
    Research Article

    Neurons generate and propagate electrical pulses called action potentials which annihilate on arrival at the axon terminal. We measure the extracellular electric field generated by propagating and annihilating action potentials and find that on annihilation, action potentials expel a local discharge. The discharge at the axon terminal generates an inhomogeneous electric field that immediately influences target neurons and thus provokes ephaptic coupling. Our measurements are quantitatively verified by a powerful analytical model which reveals excitation and inhibition in target neurons, depending on position and morphology of the source-target arrangement. Our model is in full agreement with experimental findings on ephaptic coupling at the well-studied Basket cell-Purkinje cell synapse. It is able to predict ephaptic coupling for any other synaptic geometry as illustrated by a few examples.