Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

Abstract

The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27-associated pathologies we performed proteomics in rat primary neurons to identify SNX27-dependent cargoes, and identified proteins linked to excitotoxicity, epilepsy, intellectual disabilities and working memory deficits. Focusing on the synaptic adhesion molecule LRFN2, we established that SNX27 binds to LRFN2 and regulates its endosomal sorting. Furthermore, LRFN2 associates with AMPA receptors and knockdown of LRFN2 results in decreased surface AMPA receptor expression, reduced synaptic activity, and attenuated hippocampal long-term potentiation. Overall, our study provides an additional mechanism by which SNX27 can control AMPA receptor-mediated synaptic transmission and plasticity indirectly through the sorting of LRFN2 and offers molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD026289 with the raw and filtered data also available in Supplementary File 1.

The following data sets were generated

Article and author information

Author details

  1. Kirsty J McMillan

    School of Biochemistry, University of Bristol, Bristol, United Kingdom
    For correspondence
    kirsty.mcmillan@bristol.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Paul J Banks

    School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Francesca L N Hellel

    School of Biochemistry, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Ruth E Carmichael

    School of Biochemistry, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2665-2966
  5. Thomas Clairfeuille

    Institute for Molecular Bioscience, University of Queensland, Queensland, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Ashley J Evans

    School of Biochemistry, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6658-2176
  7. Kate J Heesom

    Proteomics Facility, Faculty of Biomedical Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5418-5392
  8. Philip Lewis

    Proteomics Facility, Faculty of Biomedical Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2868-2459
  9. Brett M Collins

    Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6070-3774
  10. Zafar Bashir

    Proteomics Facility, Faculty of Biomedical Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Jeremy M Henley

    School of Biochemistry, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3589-8335
  12. Kevin Wilkinson

    School of Biochemistry, University of Bristol, Bristol, United Kingdom
    For correspondence
    Kevin.Wilkinson@bristol.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8115-8592
  13. Peter J Cullen

    Biomedical Sciences Building, University of Bristol, Bristol, United Kingdom
    For correspondence
    Pete.Cullen@bristol.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9070-8349

Funding

Medical Research Council (MR/L007363/1)

  • Peter J Cullen

Medical Research Council (MR/P018807/1)

  • Peter J Cullen

Wellcome Trust (104568/Z/14/2)

  • Peter J Cullen

Lister Institute of Preventive Medicine

  • Peter J Cullen

National Health and Medical Research Council (APP1136021)

  • Brett M Collins

National Health and Medical Research Council (APP1099114)

  • Brett M Collins

Biotechnology and Biological Sciences Research Council (BB/R00787X/1)

  • Jeremy M Henley
  • Kevin Wilkinson

Royal Society (RSRP\R1\211004)

  • Peter J Cullen

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

Ethics

Animal experimentation: All animal procedures were conducted in accordance with the United Kingdom Animals Scientific Procedures Act (1986) and associated guidelines. All efforts were made to minimise suffering and number of animals used.

Reviewing Editor

  1. Adam Linstedt, Carnegie Mellon University, United States

Publication history

  1. Received: May 28, 2020
  2. Accepted: June 23, 2021
  3. Accepted Manuscript published: July 12, 2021 (version 1)
  4. Version of Record published: July 21, 2021 (version 2)

Copyright

© 2021, McMillan 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. Kirsty J McMillan
  2. Paul J Banks
  3. Francesca L N Hellel
  4. Ruth E Carmichael
  5. Thomas Clairfeuille
  6. Ashley J Evans
  7. Kate J Heesom
  8. Philip Lewis
  9. Brett M Collins
  10. Zafar Bashir
  11. Jeremy M Henley
  12. Kevin Wilkinson
  13. Peter J Cullen
(2021)
Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2
eLife 10:e59432.
https://doi.org/10.7554/eLife.59432
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