1. Cell Biology
  2. Neuroscience
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Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin

  1. Julie Bruyère
  2. Yah-Se Abada
  3. Hélène Marine Vitet
  4. Gaëlle Fontaine
  5. Jean-Christophe Deloulme
  6. Aurélia Cès
  7. Eric Denarier
  8. Karin Pernet-Gallay
  9. Annie Andrieux
  10. Sandrine Humbert
  11. Marie-Claude Potier
  12. Benoît Delatour
  13. Frédéric Saudou  Is a corresponding author
  1. University Grenoble Alpes, France
  2. Sorbonne Université, France
  3. Institut du Cerveau et de la Moelle épinière, ICM, France
Research Article
  • Cited 3
  • Views 1,299
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Cite this article as: eLife 2020;9:e56371 doi: 10.7554/eLife.56371

Abstract

Studies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the evidence has not been consistent. In particular, signaling pathways controlling APP transport to the synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), the scaffolding protein involved in Huntington's disease, regulates neuritic transport of APP, we used a microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the pre- and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic density. Ablating in vivo HTT phosphorylation in APPPS1 mice, which overexpress APP, reduced presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis.

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. Julie Bruyère

    INSERM U1216, Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, France
    Competing interests
    No competing interests declared.
  2. Yah-Se Abada

    Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Université, Paris, France
    Competing interests
    No competing interests declared.
  3. Hélène Marine Vitet

    INSERM U1216, Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, France
    Competing interests
    No competing interests declared.
  4. Gaëlle Fontaine

    Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Université, Paris, France
    Competing interests
    No competing interests declared.
  5. Jean-Christophe Deloulme

    Inserm U 1216 Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2234-5865
  6. Aurélia Cès

    Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Université, Paris, France
    Competing interests
    No competing interests declared.
  7. Eric Denarier

    Inserm U 1216 Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4169-397X
  8. Karin Pernet-Gallay

    INSERM U1216, Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, France
    Competing interests
    No competing interests declared.
  9. Annie Andrieux

    Inserm U1216, CEA, Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4022-6405
  10. Sandrine Humbert

    INSERM U1216, Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, France
    Competing interests
    No competing interests declared.
  11. Marie-Claude Potier

    Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France
    Competing interests
    No competing interests declared.
  12. Benoît Delatour

    Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Université, Paris, France
    Competing interests
    No competing interests declared.
  13. Frédéric Saudou

    INSERM U1216, Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, France
    For correspondence
    frederic.saudou@inserm.fr
    Competing interests
    Frédéric Saudou, is on the scientific advisory board of Servier (Neurosciences Department) and a consultant for TEVA and Wave Life Sciences. The other authors declare that they have no competing interests..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6107-1046

Funding

Agence Nationale de la Recherche (ANR-12-MALZ-0004 HuntAbeta)

  • Frédéric Saudou

Agence Nationale de la Recherche (ANR-15-IDEX-02 NeuroCoG)

  • Frédéric Saudou

Agence Nationale de la Recherche (ANR-10-IAIHU-06)

  • Marie-Claude Potier

Fondation pour la Recherche Médicale (DEQ20170336752)

  • Sandrine Humbert

Fondation pour la Recherche Médicale (FDT201904008035)

  • Hélène Marine Vitet

Fondation pour la Recherche Médicale (DEI20151234418)

  • Frédéric Saudou

Fondation pour la Recherche sur le Cerveau

  • Frédéric Saudou

INSERM (AGEMED)

  • Frédéric Saudou

Fondation Bettencourt Schueller

  • Frédéric Saudou

Association Huntington France

  • Hélène Marine Vitet

Agence Nationale de la Recherche (ANR-12-MALZ-0004 HuntAbeta)

  • Marie-Claude Potier

INSERM (AGEMED)

  • Sandrine Humbert

Agence Nationale de la Recherche (ANR-14-CE35-0027-01 PASSAGE)

  • Frédéric Saudou

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

Ethics

Animal experimentation: Animals were held in accordance with the French Animal Welfare Act and the EU legislation (Council Directive 86/609/EEC) and the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. The French Ministry of Agriculture and the local ethics committee gave specific authorization (authorization no. 04594.02) to BD to conduct the experiments described in the present study.

Reviewing Editor

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

Publication history

  1. Received: February 25, 2020
  2. Accepted: May 11, 2020
  3. Accepted Manuscript published: May 26, 2020 (version 1)
  4. Version of Record published: June 3, 2020 (version 2)

Copyright

© 2020, Bruyère 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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