Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2
- University of Bristol, United Kingdom
- University of Queensland, Australia
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.
Article and author information
Author details
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.
Reviewing Editor
- Adam Linstedt, Carnegie Mellon University, United States
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.
Version history
- Received: May 28, 2020
- Accepted: June 23, 2021
- Accepted Manuscript published: July 12, 2021 (version 1)
- 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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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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