Inhibition of oxidative stress in cholinergic projection neurons fully rescues aging associated olfactory circuit degeneration in Drosophila

  1. Ashiq Hussain
  2. Atefeh Pooryasin
  3. Mo Zhang
  4. Laura F Loschek
  5. Marco La Fortezza
  6. Anja B Friedrich
  7. Catherine-Marie Blais
  8. Habibe K Üçpunar
  9. Vicente A Yépez
  10. Martin Lehmann
  11. Nicolas Gompel
  12. Julien Gagneur
  13. Stephan J Sigrist
  14. Ilona C Grunwald Kadow  Is a corresponding author
  1. Technical University of Munich, Germany
  2. Free University of Berlin, Germany
  3. Max-Planck Institute of Neurobiology, Germany
  4. Ludwig-Maximilians-Universität München, Germany
  5. Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Germany

Abstract

Loss of the sense of smell is among the first signs of natural aging and neurodegenerative diseases such as Alzheimer's and Parkinson's. Cellular and molecular mechanisms promoting this smell loss are not understood. Here, we show that Drosophila melanogaster also loses olfaction before vision with age. Within the olfactory circuit, cholinergic projection neurons show a reduced odor response accompanied by a defect in axonal integrity and reduction in synaptic marker proteins. Using behavioral functional screening, we pinpoint that expression of the mitochondrial reactive oxygen scavenger SOD2 in cholinergic projection neurons is necessary and sufficient to prevent smell degeneration in aging flies. Together, our data show that oxidative stress induced axonal degeneration in a single class of neurons drives the functional decline of an entire neural network and the behavior it controls. Given the important role of the cholinergic system in neurodegeneration, the fly olfactory system could be a useful model for the identification of drug targets.

Article and author information

Author details

  1. Ashiq Hussain

    School of Life Sciences, Technical University of Munich, Freising, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Atefeh Pooryasin

    Institute of Biology, Free University of Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Mo Zhang

    Max-Planck Institute of Neurobiology, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Laura F Loschek

    Max-Planck Institute of Neurobiology, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Marco La Fortezza

    Ludwig-Maximilians-Universität München, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Anja B Friedrich

    School of Life Sciences, Technical University of Munich, Freising, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Catherine-Marie Blais

    School of Life Sciences, Technical University of Munich, Freising, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Habibe K Üçpunar

    Max-Planck Institute of Neurobiology, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Vicente A Yépez

    Department of Informatics, Technical University of Munich, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Martin Lehmann

    Department of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Nicolas Gompel

    Ludwig-Maximilians-Universität München, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Julien Gagneur

    Department of Informatics, Technical University of Munich, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8924-8365
  13. Stephan J Sigrist

    Institute of Biology, Free University of Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Ilona C Grunwald Kadow

    School of Life Sciences, Technical University of Munich, Freising, Germany
    For correspondence
    ilona.grunwald@tum.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9085-4274

Funding

H2020 European Research Council (FlyContext)

  • Ilona C Grunwald Kadow

European Molecular Biology Organization (EMBO Young Investigator Small Grant)

  • Ilona C Grunwald Kadow

Max-Planck-Gesellschaft (Open-access funding)

  • Ilona C Grunwald Kadow

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

Reviewing Editor

  1. Patrik Verstreken, VIB-KU Leuven, Belgium

Publication history

  1. Received: September 14, 2017
  2. Accepted: January 16, 2018
  3. Accepted Manuscript published: January 18, 2018 (version 1)
  4. Version of Record published: January 30, 2018 (version 2)

Copyright

© 2018, Hussain 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

  • 4,244
    Page views
  • 543
    Downloads
  • 13
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

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. Ashiq Hussain
  2. Atefeh Pooryasin
  3. Mo Zhang
  4. Laura F Loschek
  5. Marco La Fortezza
  6. Anja B Friedrich
  7. Catherine-Marie Blais
  8. Habibe K Üçpunar
  9. Vicente A Yépez
  10. Martin Lehmann
  11. Nicolas Gompel
  12. Julien Gagneur
  13. Stephan J Sigrist
  14. Ilona C Grunwald Kadow
(2018)
Inhibition of oxidative stress in cholinergic projection neurons fully rescues aging associated olfactory circuit degeneration in Drosophila
eLife 7:e32018.
https://doi.org/10.7554/eLife.32018

Further reading

    1. Neuroscience
    Andrea Merseburg et al.
    Research Article

    De novo mutations in voltage- and ligand-gated channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies, which often fail to respond to classic antiseizure medications. Here, we examine two knock-in mouse models replicating de novo sequence variations in the HCN1 voltage-gated channel gene, p.G391D and p.M153I (Hcn1G380D/+ and Hcn1M142I/+ in mouse), associated with severe drug-resistant neonatal- and childhood-onset epilepsy, respectively. Heterozygous mice from both lines displayed spontaneous generalized tonic-clonic seizures. Animals replicating the p.G391D variant had an overall more severe phenotype, with pronounced alterations in the levels and distribution of HCN1 protein, including disrupted targeting to the axon terminals of basket cell interneurons. In line with clinical reports from patients with pathogenic HCN1 sequence variations, administration of the antiepileptic Na+ channel antagonists lamotrigine and phenytoin resulted in the paradoxical induction of seizures in both mouse lines, consistent with an effect to further impair inhibitory neuron function. We also show that these variants can render HCN1 channels unresponsive to classic antagonists, indicating the need to screen mutated channels to identify novel compounds with diverse mechanism of action. Our results underscore the necessity of tailoring effective therapies for specific channel gene variants, and how strongly validated animal models may provide an invaluable tool towards reaching this objective.

    1. Neuroscience
    Danilo Menicucci et al.
    Research Article

    Sleep and plasticity are highly interrelated, as sleep slow oscillations and sleep spindles are associated with consolidation of Hebbian-based processes. However, in adult humans, visual cortical plasticity is mainly sustained by homeostatic mechanisms, for which the role of sleep is still largely unknown. Here we demonstrate that non-REM sleep stabilizes homeostatic plasticity of ocular dominance induced in adult humans by short-term monocular deprivation: the counter-intuitive and otherwise transient boost of the deprived eye was preserved at the morning awakening (>6 hours after deprivation). Subjects exhibiting a stronger boost of the deprived eye after sleep had increased sleep spindle density in frontopolar electrodes, suggesting the involvement of distributed processes. Crucially, the individual susceptibility to visual homeostatic plasticity soon after deprivation correlated with the changes in sleep slow oscillations and spindle power in occipital sites, consistent with a modulation in early occipital visual cortex.