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

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

doi:10.7554/eLife.59432

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

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

^*Corresponding author for this work

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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.

Original language	English
Article number	e59432
Number of pages	32
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.59432
Publication status	Published - 12 Jul 2021

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This is the final published version of the article (version of record). It first appeared online via eLife Sciences Publications at https://elifesciences.org/articles/59432 . Please refer to any applicable terms of use of the publisher.
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McMillan, K. J., Banks, P. J., Hellel, F. L., Carmichael, R. E., Clairfeuille, T., Evans, A. J., Heesom, K. J., Lewis, P., Collins, B. M., Bashir, Z. I., Henley, J. M., Wilkinson, K. A., & Cullen, P. J. (2021). Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2. eLife, 10, Article e59432. https://doi.org/10.7554/eLife.59432

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title = "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.",

author = "McMillan, {Kirsty J} and Banks, {Paul J} and Hellel, {Francesca Ln} and Carmichael, {Ruth E} and Thomas Clairfeuille and Evans, {Ashley J} and Heesom, {Kate J} and Philip Lewis and Collins, {Brett M} and Bashir, {Zafar I} and Henley, {Jeremy M} and Wilkinson, {Kevin A} and Cullen, {Peter J}",

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T1 - Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

AU - McMillan, Kirsty J

AU - Banks, Paul J

AU - Hellel, Francesca Ln

AU - Carmichael, Ruth E

AU - Clairfeuille, Thomas

AU - Evans, Ashley J

AU - Heesom, Kate J

AU - Lewis, Philip

AU - Collins, Brett M

AU - Bashir, Zafar I

AU - Henley, Jeremy M

AU - Wilkinson, Kevin A

AU - Cullen, Peter J

PY - 2021/7/12

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N2 - 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.

AB - 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.

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M3 - Article (Academic Journal)

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SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

M1 - e59432

ER -

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

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