1. Chromosomes and Gene Expression
  2. Neuroscience
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HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration

  1. Alicia Tapias
  2. David Lázaro
  3. Bo-Kun Yin
  4. Seyed Mohammad Mahdi Rasa
  5. Anna Krepelova
  6. Erika Kelmer Sacramento
  7. Paulius Grigaravicius
  8. Philipp Koch
  9. Joanna Kirkpatrick
  10. Alessandro Ori
  11. Francesco Neri
  12. Zhao-Qi Wang  Is a corresponding author
  1. Leibniz Institute on Ageing - Fritz Lipmann Institute, Germany
  2. Leibniz Institute on Aging - Fritz Lipmann Institute, Germany
Research Article
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Cite this article as: eLife 2021;10:e61531 doi: 10.7554/eLife.61531

Abstract

Brain homeostasis is regulated by the viability and functionality of neurons. HAT (histone acetyltransferase) and HDAC (histone deacetylase) inhibitors have been applied to treat neurological deficits in humans; yet, the epigenetic regulation in neurodegeneration remains elusive. Mutations of HAT cofactor TRRAP (Transformation/translation domain-associated protein) cause human neuropathies, including psychosis, intellectual disability, autism and epilepsy, with unknown mechanism. Here we show that Trrap deletion in Purkinje neurons results in neurodegeneration of old mice. Integrated transcriptomics, epigenomics and proteomics reveal that TRRAP via SP1 conducts a conserved transcriptomic program. TRRAP is required for SP1 binding at the promoter proximity of target genes, especially microtubule dynamics. The ectopic expression of Stathmin3/4 ameliorates defects of TRRAP-deficient neurons, indicating that the microtubule dynamics is particularly vulnerable to the action of SP1 activity. This study unravels a network linking three well-known, but up-to-date unconnected, signaling pathways, namely TRRAP, HAT and SP1 with microtubule dynamics, in neuroprotection.

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Author details

  1. Alicia Tapias

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  2. David Lázaro

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  3. Bo-Kun Yin

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  4. Seyed Mohammad Mahdi Rasa

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6850-8909

  5. Anna Krepelova

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  6. Erika Kelmer Sacramento

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  7. Paulius Grigaravicius

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  8. Philipp Koch

    Core Facility Life Science Computing, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2825-7943

  9. Joanna Kirkpatrick

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  10. Alessandro Ori

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3046-0871

  11. Francesco Neri

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  12. Zhao-Qi Wang

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    For correspondence
    Zhao-Qi.Wang@leibniz-fli.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8336-3485

Funding

Leibniz Publik

  • Zhao-Qi Wang

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

Ethics

Animal experimentation: Animal experiments were conducted according to German animal welfare legislation, and the protocol is approved by Thüringen Landesamt für Verbraucherschutz (TLV) (03-042/16), Germany.

Reviewing Editor

  1. Jeremy J Day, University of Alabama at Birmingham, United States

Publication history

  1. Received: July 28, 2020
  2. Accepted: February 16, 2021
  3. Accepted Manuscript published: February 17, 2021 (version 1)

Copyright

© 2021, Tapias 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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