Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate that UBQLN2 regulates the domesticated gag-pol retrotransposon 'paternally expressed gene 10' (PEG10) in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated 'nucleocapsid' fragment, which uniquely localizes to the nucleus and changes the expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.

Data availability

Figure 6 - Source Data 1 contains the normalized counts from RNA-Seq data used to generate figures. Figure 8 - Source Data 1 contains the abundance counts from proteomics data used to generate figures. Sequencing data have been deposited in the Gene Expression Omnibus (GEO) at GSE227789. Proteomics data is available on PRIDE at PXD031964. Analysis code for microscopy quantitation can be obtained from https://github.com/jwtay1/PEG10-image-analysis/. All other data is available in the manuscript or source materials. Correspondence and material requests should be directed to A. M. Whiteley (alexandra.whiteley@colorado.edu).

The following data sets were generated

Article and author information

Author details

  1. Holly H Black

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1383-136X
  2. Jessica L Hanson

    Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
  3. Julia E Roberts

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
  4. Shannon N Leslie

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
  5. Will Campodonico

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9098-5266
  6. Christopher C Ebmeier

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7940-6190
  7. G Aaron Holling

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
  8. Jian Wei Tay

    Biofrontiers Institute, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8634-5039
  9. Autumn M Matthews

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
  10. Elizabeth Ung

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
  11. Cristina I Lau

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0850-9963
  12. Alexandra Whiteley

    Department of Biochemistry, University of Colorado Boulder, Boulder, United States
    For correspondence
    alexandra.whiteley@colorado.edu
    Competing interests
    Alexandra Whiteley, The University of Colorado, Boulder, has a patent pending for the use of PEG10 inhibitors on which the author is an inventor..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4144-7605

Funding

National Institute of General Medical Sciences (T32GM142607)

  • Julia E Roberts
  • Autumn M Matthews

National Cancer Institute (T32CA174648)

  • G Aaron Holling

Biological Sciences Initiative

  • Elizabeth Ung
  • Cristina I Lau

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

Reviewing Editor

  1. Harry T Orr, University of Minnesota, United States

Version history

  1. Preprint posted: March 27, 2022 (view preprint)
  2. Received: April 13, 2022
  3. Accepted: March 15, 2023
  4. Accepted Manuscript published: March 23, 2023 (version 1)
  5. Version of Record published: April 5, 2023 (version 2)

Copyright

© 2023, Black 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. Holly H Black
  2. Jessica L Hanson
  3. Julia E Roberts
  4. Shannon N Leslie
  5. Will Campodonico
  6. Christopher C Ebmeier
  7. G Aaron Holling
  8. Jian Wei Tay
  9. Autumn M Matthews
  10. Elizabeth Ung
  11. Cristina I Lau
  12. Alexandra Whiteley
(2023)
UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS
eLife 12:e79452.
https://doi.org/10.7554/eLife.79452

Share this article

https://doi.org/10.7554/eLife.79452

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