Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43

  1. Dongeun Heo
  2. Jonathan Ling
  3. Gian C Molina-Castro
  4. Abraham J Langseth
  5. Ari Waisman
  6. Klaus-Armin Nave
  7. Wiebke Möbius
  8. Phil C Wong
  9. Dwight E Bergles  Is a corresponding author
  1. Johns Hopkins University School of Medicine, United States
  2. Johns Hopkins School of Medicine, United States
  3. Johannes Gutenberg University, Germany
  4. Max Planck Institute of Experimental Medicine, Germany

Abstract

Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43 deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult CNS induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.

Data availability

Bulk RNA-seq data of P30 FACS-isolated oligodendrocytes from Mobp-TDP43 and Mog-TDP43 mouse lines will be deposited to GEO. Processed data, including the raw count number, normalized counts, and FPKM values, are provided as Supplementary Data (Supplementary Data - Differential gene expression Excel file of bulk RNA-Seq.xlsx).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Dongeun Heo

    The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4913-2253
  2. Jonathan Ling

    The Solomon H Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1927-9729
  3. Gian C Molina-Castro

    The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0700-4042
  4. Abraham J Langseth

    The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  5. Ari Waisman

    Institute for Molecular Medicine, Johannes Gutenberg University, Mainz, Germany
    Competing interests
    No competing interests declared.
  6. Klaus-Armin Nave

    Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
    Competing interests
    Klaus-Armin Nave, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8724-9666
  7. Wiebke Möbius

    Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2902-7165
  8. Phil C Wong

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  9. Dwight E Bergles

    The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    dbergles@jhmi.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7133-7378

Funding

National Institutes of Health (R01 AG072305)

  • Dwight E Bergles

National Multiple Sclerosis Society

  • Dwight E Bergles

National Institutes of Health (F31NS110204)

  • Dongeun Heo

European Research Council (MyeliNANO)

  • Klaus-Armin Nave

Deutsche Forschungsgemeinschaft (DFG-TRR274)

  • Klaus-Armin Nave

Target ALS

  • Dwight E Bergles

Dr. Miriam and Sheldon G Adelson Medical Research Foundation

  • Dwight E Bergles

Max-Planck-Institute of Experimental Medicine (open access funding)

  • Wiebke Möbius

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

Reviewing Editor

  1. Beth Stevens, Boston Children's Hospital, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations by the Institutional Animal Care and Use Committee (IACUC) of the Johns Hopkins School of Medicine under protocols (MO17M338, MO17M268, MO20M206, and MO20M344). All survival surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering. All terminal experiments were carried out under sodium pentobarbital anesthesia.

Version history

  1. Received: November 3, 2021
  2. Preprint posted: November 9, 2021 (view preprint)
  3. Accepted: March 18, 2022
  4. Accepted Manuscript published: March 21, 2022 (version 1)
  5. Version of Record published: March 31, 2022 (version 2)

Copyright

© 2022, Heo 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. Dongeun Heo
  2. Jonathan Ling
  3. Gian C Molina-Castro
  4. Abraham J Langseth
  5. Ari Waisman
  6. Klaus-Armin Nave
  7. Wiebke Möbius
  8. Phil C Wong
  9. Dwight E Bergles
(2022)
Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43
eLife 11:e75230.
https://doi.org/10.7554/eLife.75230

Share this article

https://doi.org/10.7554/eLife.75230

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