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

• DOI: 10.7554/elife.59432
• Publication Date: 2021-07-12T16:00:25Z
• Authors: Kirsty J McMillan; Paul J Banks; Francesca LN Hellel; Ruth E Carmichael; Thomas Clairfeuille; Ashley J Evans; Kate J Heesom; Philip Lewis; Brett M Collins; Zafar I Bashir; Jeremy M Henley; Kevin A Wilkinson; Peter J Cullen
• Keywords: Proteomics; 570; QH301-705.5; Science; Long-Term Potentiation; 610; Nerve Tissue Proteins; Endosomes; Hippocampus; Synaptic Transmission; 03 medical and health sciences; Animals; Humans; Receptors, AMPA; Biology (General); AMPA receptors; SNX27; Sorting Nexins; Neurons; Memory Disorders; 0303 health sciences; Membrane Glycoproteins; membrane trafficking; Q; R; Cell Biology; Rats; Protein Transport; LRFN2; Medicine

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.