The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

Jeffrey N. Savas; Luís F. Ribeiro; Keimpe D. Wierda; Rebecca Wright; Laura A. DeNardo-Wilke; Heather C. Rice; Ingrid Chamma; Yi Zhi Wang; Roland Zemla; Mathieu Lavallée-Adam; Kristel M. Vennekens; Matthew L. O'Sullivan; Joseph K. Antonios; Elizabeth A. Hall; Olivier Thoumine; Alan D. Attie; John R. Yates; Anirvan Ghosh; Joris de Wit

doi:10.1016/j.neuron.2015.08.007

The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

Jeffrey N. Savas, Luís F. Ribeiro, Keimpe D. Wierda, Rebecca Wright, Laura A. DeNardo-Wilke, Heather C. Rice, Ingrid Chamma, Yi Zhi Wang, Roland Zemla, Mathieu Lavallée-Adam, Kristel M. Vennekens, Matthew L. O'Sullivan, Joseph K. Antonios, Elizabeth A. Hall, Olivier Thoumine, Alan D. Attie, John R. Yates^*, Anirvan Ghosh, Joris de Wit

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here, we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1-knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1-deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and -function defects underlying synaptopathies. The formation, function, and plasticity of synapses require changes in receptor composition. Savas et al. identify the sorting receptor SorCS1 as a major regulator of receptor trafficking and show that SorCS1 maintains synaptic levels of key adhesion and neurotransmitter receptors.

Original language	English (US)
Pages (from-to)	764-780
Number of pages	17
Journal	Neuron
Volume	87
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2015.08.007
State	Published - Aug 19 2015

Funding

We thank Patrik Verstreken, Rose Goodchild, Matthew Holt, Bassem Hassan, Kevin L\u0171thy, Christopher Parkhurst, and Peter Penzes for comments on the manuscript; Casper Hoogenraad, Wim Annaert, and Ragna Sannerud for reagents and advice; Davide Comoletti for providing Nrxn-ecto-Fc stable cell lines; and Sung Kyu Park, Merve Oney, Christine Wu, Mohit Patel, Margaret Butko, Jacqueline Benthuysen, and Max Caccese for technical assistance. This work was supported by NIH awards F32AG039127 and 4 R00DC013805-02 (J.N.S.); Marie Sklodowska-Curie postdoctoral fellowship H2020-MSCA-IF-2014 (L.F.R.); a postdoctoral fellowship from Fonds de Recherche du Qu\u00E9bec \u2013 Nature et Technologies (M.L.A.); Conseil R\u00E9gional Aquitaine (I.C. and O.T.); Fondation pour la Recherche M\u00E9dicale and Agence Nationale de la Recherche (O.T.); NIH grants R01MH068578 and R01NS067216 (A.G.); NIH grants P41 GM103533 and R01 MH067880 (J.R.Y.); and a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation, a European Research Council Starting Grant (311083), and a FWO Odysseus Grant (J.d.W.). The .raw files, search and quantitative results, and complete parameter files for all MS experiments are publicly available at http://fields.scripps.edu/published/SorCS_NRXN/ .

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General Neuroscience

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Savas, J. N., Ribeiro, L. F., Wierda, K. D., Wright, R., DeNardo-Wilke, L. A., Rice, H. C., Chamma, I., Wang, Y. Z., Zemla, R., Lavallée-Adam, M., Vennekens, K. M., O'Sullivan, M. L., Antonios, J. K., Hall, E. A., Thoumine, O., Attie, A. D., Yates, J. R., Ghosh, A., & de Wit, J. (2015). The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors. Neuron, 87(4), 764-780. https://doi.org/10.1016/j.neuron.2015.08.007

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title = "The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors",

abstract = "The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here, we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1-knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1-deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and -function defects underlying synaptopathies. The formation, function, and plasticity of synapses require changes in receptor composition. Savas et al. identify the sorting receptor SorCS1 as a major regulator of receptor trafficking and show that SorCS1 maintains synaptic levels of key adhesion and neurotransmitter receptors.",

author = "Savas, {Jeffrey N.} and Ribeiro, {Lu{\'i}s F.} and Wierda, {Keimpe D.} and Rebecca Wright and DeNardo-Wilke, {Laura A.} and Rice, {Heather C.} and Ingrid Chamma and Wang, {Yi Zhi} and Roland Zemla and Mathieu Lavall{\'e}e-Adam and Vennekens, {Kristel M.} and O'Sullivan, {Matthew L.} and Antonios, {Joseph K.} and Hall, {Elizabeth A.} and Olivier Thoumine and Attie, {Alan D.} and Yates, {John R.} and Anirvan Ghosh and {de Wit}, Joris",

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Savas, JN, Ribeiro, LF, Wierda, KD, Wright, R, DeNardo-Wilke, LA, Rice, HC, Chamma, I, Wang, YZ, Zemla, R, Lavallée-Adam, M, Vennekens, KM, O'Sullivan, ML, Antonios, JK, Hall, EA, Thoumine, O, Attie, AD, Yates, JR, Ghosh, A & de Wit, J 2015, 'The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors', Neuron, vol. 87, no. 4, pp. 764-780. https://doi.org/10.1016/j.neuron.2015.08.007

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T1 - The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

AU - Savas, Jeffrey N.

AU - Ribeiro, Luís F.

AU - Wierda, Keimpe D.

AU - Wright, Rebecca

AU - DeNardo-Wilke, Laura A.

AU - Rice, Heather C.

AU - Chamma, Ingrid

AU - Wang, Yi Zhi

AU - Zemla, Roland

AU - Lavallée-Adam, Mathieu

AU - Vennekens, Kristel M.

AU - O'Sullivan, Matthew L.

AU - Antonios, Joseph K.

AU - Hall, Elizabeth A.

AU - Thoumine, Olivier

AU - Attie, Alan D.

AU - Yates, John R.

AU - Ghosh, Anirvan

AU - de Wit, Joris

PY - 2015/8/19

Y1 - 2015/8/19

N2 - The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here, we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1-knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1-deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and -function defects underlying synaptopathies. The formation, function, and plasticity of synapses require changes in receptor composition. Savas et al. identify the sorting receptor SorCS1 as a major regulator of receptor trafficking and show that SorCS1 maintains synaptic levels of key adhesion and neurotransmitter receptors.

AB - The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here, we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1-knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1-deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and -function defects underlying synaptopathies. The formation, function, and plasticity of synapses require changes in receptor composition. Savas et al. identify the sorting receptor SorCS1 as a major regulator of receptor trafficking and show that SorCS1 maintains synaptic levels of key adhesion and neurotransmitter receptors.

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The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

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