1. Cell Biology
  2. Neuroscience

Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2

  1. Sang Hwa Kim  Is a corresponding author
  2. Kye D Nichols
  3. Eric N Anderson
  4. Yining Liu
  5. Nandini Ramesh
  6. Weiyan Jia
  7. Connor J Kuerbis
  8. Mark Scalf
  9. Lloyd M Smith
  10. Udai Bhan Pandey
  11. Randal S Tibbetts  Is a corresponding author
  1. University of Wisconsin-Madison, United States
  2. University of Pittsburgh Medical Center, United States
https://doi.org/10.7554/eLife.84382
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Cite this article
  1. Sang Hwa Kim
  2. Kye D Nichols
  3. Eric N Anderson
  4. Yining Liu
  5. Nandini Ramesh
  6. Weiyan Jia
  7. Connor J Kuerbis
  8. Mark Scalf
  9. Lloyd M Smith
  10. Udai Bhan Pandey
  11. Randal S Tibbetts
(2023)
Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2
eLife 12:e84382.
https://doi.org/10.7554/eLife.84382
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Abstract

Mutations in the ubiquitin (Ub) chaperone Ubiquilin 2 (UBQLN2) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2ALS) trigger heat stress-dependent neurodegeneration in Drosophila. A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage of Unc-5 or its coreceptor Dcc/frazzled diminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2ALS alleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2ALS knockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2ALS alleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of UNC5B and DCC. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.

Data availability

The RNA sequencing raw dataset has been deposited to Dryad and is accessible at https://doi.org/10.5061/dryad.tdz08kq39. All data generated or analyzed during this study are included in the manuscript.

The following data sets were generated

Article and author information

Author details

  1. Sang Hwa Kim

    Department of Human Oncology, University of Wisconsin-Madison, Madison, United States
    For correspondence
    shkim9@wisc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9245-4514

  2. Kye D Nichols

    Department of Human Oncology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Eric N Anderson

    Department of Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Yining Liu

    Department of Human Oncology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2632-7119

  5. Nandini Ramesh

    Department of Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Weiyan Jia

    Department of Human Oncology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Connor J Kuerbis

    Department of Human Oncology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Mark Scalf

    Department of Chemistry, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Lloyd M Smith

    Department of Chemistry, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6652-8639

  10. Udai Bhan Pandey

    Department of Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6267-0179

  11. Randal S Tibbetts

    Department of Human Oncology, University of Wisconsin-Madison, Madison, United States
    For correspondence
    rstibbetts@wisc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2245-2297

Funding

National Institute on Aging (R21 AG065896-01A1)

  • Sang Hwa Kim

National Institutes of Health (1RF1AG069483-01A1)

  • Randal S Tibbetts

National Cancer Institute (1R21 NS101661-01-A1)

  • Randal S Tibbetts

ALS Association (Proteostatic regulation by Ubiquilins in ALS)

  • Randal S Tibbetts

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

Reviewing Editor

  1. Jeannie Chin, Baylor College of Medicine, United States

Version history

  1. Received: October 22, 2022
  2. Preprint posted: November 1, 2022 (view preprint)
  3. Accepted: April 6, 2023
  4. Accepted Manuscript published: April 11, 2023 (version 1)
  5. Version of Record published: April 28, 2023 (version 2)

Copyright

© 2023, Kim 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. Sang Hwa Kim
  2. Kye D Nichols
  3. Eric N Anderson
  4. Yining Liu
  5. Nandini Ramesh
  6. Weiyan Jia
  7. Connor J Kuerbis
  8. Mark Scalf
  9. Lloyd M Smith
  10. Udai Bhan Pandey
  11. Randal S Tibbetts
(2023)
Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2
eLife 12:e84382.
https://doi.org/10.7554/eLife.84382

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