A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism

  1. Elliot Imler
  2. Jin Sang Pyon
  3. Selina Kindelay
  4. Meaghan Torvund
  5. Yong-quan Zhang
  6. Sreeganga S Chandra
  7. Konrad E Zinsmaier  Is a corresponding author
  1. University of Arizona, United States
  2. Yale University, United States

Abstract

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Elliot Imler

    Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jin Sang Pyon

    Undergraduate Program in Neuroscience and Cognitive Science Department of Molecular, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Selina Kindelay

    Undergraduate Program in Neuroscience and Cognitive Science Department of Molecular, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Meaghan Torvund

    Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yong-quan Zhang

    Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sreeganga S Chandra

    Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9035-1733
  7. Konrad E Zinsmaier

    Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States
    For correspondence
    kez4@email.arizona.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9992-6238

Funding

National Institute of Neurological Disorders and Stroke (R01NS083849)

  • Sreeganga S Chandra

National Institute of Neurological Disorders and Stroke (R21NS094809)

  • Konrad E Zinsmaier

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

Reviewing Editor

  1. Lee L Rubin, Harvard Stem Cell Institute, Harvard University, United States

Version history

  1. Received: March 6, 2019
  2. Accepted: October 29, 2019
  3. Accepted Manuscript published: October 30, 2019 (version 1)
  4. Version of Record published: December 6, 2019 (version 2)

Copyright

© 2019, Imler 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. Elliot Imler
  2. Jin Sang Pyon
  3. Selina Kindelay
  4. Meaghan Torvund
  5. Yong-quan Zhang
  6. Sreeganga S Chandra
  7. Konrad E Zinsmaier
(2019)
A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism
eLife 8:e46607.
https://doi.org/10.7554/eLife.46607

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https://doi.org/10.7554/eLife.46607

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