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.

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.

Metrics

  • 1,429
    views
  • 223
    downloads
  • 13
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

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

Further reading

    1. Neuroscience
    GVS Devakinandan, Mark Terasaki, Adish Dani
    Research Article

    Specialized chemosensory signals elicit innate social behaviors in individuals of several vertebrate species, a process that is mediated via the accessory olfactory system (AOS). The AOS comprising the peripheral sensory vomeronasal organ has evolved elaborate molecular and cellular mechanisms to detect chemo signals. To gain insight into the cell types, developmental gene expression patterns, and functional differences amongst neurons, we performed single-cell transcriptomics of the mouse vomeronasal sensory epithelium. Our analysis reveals diverse cell types with gene expression patterns specific to each, which we made available as a searchable web resource accessed from https://www.scvnoexplorer.com. Pseudo-time developmental analysis indicates that neurons originating from common progenitors diverge in their gene expression during maturation with transient and persistent transcription factor expression at critical branch points. Comparative analysis across two of the major neuronal subtypes that express divergent GPCR families and the G-protein subunits Gnai2 or Gnao1, reveals significantly higher expression of endoplasmic reticulum (ER) associated genes within Gnao1 neurons. In addition, differences in ER content and prevalence of cubic membrane ER ultrastructure revealed by electron microscopy, indicate fundamental differences in ER function.

    1. Developmental Biology
    2. Neuroscience
    Xingsen Zhao, Qihang Sun ... Xuekun Li
    Research Article

    Williams syndrome (WS; OMIM#194050) is a rare disorder, which is caused by the microdeletion of one copy of 25–27 genes, and WS patients display diverse neuronal deficits. Although remarkable progresses have been achieved, the mechanisms for these distinct deficits are still largely unknown. Here, we have shown that neural progenitor cells (NPCs) in WS forebrain organoids display abnormal proliferation and differentiation capabilities, and synapse formation. Genes with altered expression are related to neuronal development and neurogenesis. Single cell RNA-seq (scRNA-seq) data analysis revealed 13 clusters in healthy control and WS organoids. WS organoids show an aberrant generation of excitatory neurons. Mechanistically, the expression of transthyretin (TTR) are remarkably decreased in WS forebrain organoids. We have found that GTF2IRD1 encoded by one WS associated gene GTF2IRD1 binds to TTR promoter regions and regulates the expression of TTR. In addition, exogenous TTR can activate ERK signaling and rescue neurogenic deficits of WS forebrain organoids. Gtf2ird1-deficient mice display similar neurodevelopmental deficits as observed in WS organoids. Collectively, our study reveals critical function of GTF2IRD1 in regulating neurodevelopment of WS forebrain organoids and mice through regulating TTR-ERK pathway.