TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau

  1. Maxime WC Rousseaux
  2. Maria de Haro
  3. Cristian A Lasagna-Reeves
  4. Antonia De Maio
  5. Jeehye Park
  6. Paymaan Jafar-Nejad
  7. Ismael Al-Ramahi
  8. Ajay Sharma
  9. Lauren See
  10. Nan Lu
  11. Luis Vilanova-Velez
  12. Tiemo J Klisch
  13. Thomas F Westbrook
  14. Juan C Troncoso
  15. Juan Botas
  16. Huda Y Zoghbi  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. Texas Children's Hospital, United States
  3. The University of Toronto, Canada
  4. Ionis Pharmaceuticals, United States
  5. Johns Hopkins University School of Medicine, United States

Abstract

Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that α-Syn and tau overlap pathologically. The connections between α-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of α-Syn and tau. We found that TRIM28 regulates α-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and α-Syn-mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points.

Article and author information

Author details

  1. Maxime WC Rousseaux

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  2. Maria de Haro

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  3. Cristian A Lasagna-Reeves

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  4. Antonia De Maio

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.
  5. Jeehye Park

    Program in Genetics and Genome Biology, The Hospital for Sick Children, The University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  6. Paymaan Jafar-Nejad

    Ionis Pharmaceuticals, Carlsbad, United States
    Competing interests
    No competing interests declared.
  7. Ismael Al-Ramahi

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

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  9. Lauren See

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

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  11. Luis Vilanova-Velez

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  12. Tiemo J Klisch

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  13. Thomas F Westbrook

    Department of Molecular and Human Genetics, Baylor College of Medicine, Boston, United States
    Competing interests
    No competing interests declared.
  14. Juan C Troncoso

    Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  15. Juan Botas

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  16. Huda Y Zoghbi

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    For correspondence
    hzoghbi@bcm.edu
    Competing interests
    Huda Y Zoghbi, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0700-3349

Funding

Howard Hughes Medical Institute

  • Huda Y Zoghbi

Michael J. Fox Foundation for Parkinson's Research (Target Validation Program 2014)

  • Huda Y Zoghbi

Canadian Institutes of Health Research (201210MFE-290072-173743)

  • Maxime WC Rousseaux

National Institutes of Health (1K22NS092688-01)

  • Cristian A Lasagna-Reeves

National Institutes of Health (U54 HD083092)

  • Huda Y Zoghbi

National Institutes of Health (P50 NS38377)

  • Juan C Troncoso

National Institutes of Health (P50 AG05146)

  • Juan C Troncoso

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Up to five mice were housed per cage and kept on a 12 h light; 12 h dark cycle and were given water and standard rodent chow ad libitum. All procedures carried out in mice were approved by the Institutional Animal Care and Use Committee for Baylor College of Medicine and Affiliates.

Human subjects: Tissue from patients with PD, AD, PSP and control subjects were obtained from the Neuropathology Core at the Johns Hopkins Udall Centre. Tissue was obtained from consenting donors and use conformed to JHMI Institutional Review Board approved protocols.

Reviewing Editor

  1. Susan L Ackerman, Howard Hughes Medical Institute, University of California, San Diego, United States

Publication history

  1. Received: July 20, 2016
  2. Accepted: October 12, 2016
  3. Accepted Manuscript published: October 25, 2016 (version 1)
  4. Version of Record published: November 10, 2016 (version 2)

Copyright

© 2016, Rousseaux 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. Maxime WC Rousseaux
  2. Maria de Haro
  3. Cristian A Lasagna-Reeves
  4. Antonia De Maio
  5. Jeehye Park
  6. Paymaan Jafar-Nejad
  7. Ismael Al-Ramahi
  8. Ajay Sharma
  9. Lauren See
  10. Nan Lu
  11. Luis Vilanova-Velez
  12. Tiemo J Klisch
  13. Thomas F Westbrook
  14. Juan C Troncoso
  15. Juan Botas
  16. Huda Y Zoghbi
(2016)
TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau
eLife 5:e19809.
https://doi.org/10.7554/eLife.19809
  1. Further reading

Further reading

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    Research Article Updated

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