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 3rd; Anirvan Ghosh; Joris de Wit

doi:10.1016/j.neuron.2015.08.007

The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

Neuron. 2015 Aug 19;87(4):764-80. doi: 10.1016/j.neuron.2015.08.007.

Authors

Jeffrey N Savas¹, Luís F Ribeiro², Keimpe D Wierda², Rebecca Wright³, Laura A DeNardo-Wilke³, Heather C Rice², Ingrid Chamma⁴, Yi-Zhi Wang⁵, Roland Zemla⁶, Mathieu Lavallée-Adam⁷, Kristel M Vennekens², Matthew L O'Sullivan³, Joseph K Antonios³, Elizabeth A Hall⁵, Olivier Thoumine⁴, Alan D Attie⁸, John R Yates 3rd⁹, Anirvan Ghosh¹⁰, Joris de Wit¹¹

Affiliations

¹ Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
² VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
³ Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ UMR 5297, Interdisciplinary Institute for Neuroscience, University of Bordeaux and Centre National de la Recherche Scientifique, 33000 Bordeaux, France.
⁵ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁶ School of Medicine, New York University, New York, New York 10016, USA.
⁷ Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁸ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁹ Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: jyates@scripps.edu.
¹⁰ Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA; Neuroscience Discovery, F. Hoffman-La Roche, 4070 Basel, Switzerland.
¹¹ VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium. Electronic address: joris.dewit@cme.vib-kuleuven.be.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium-Binding Proteins
Cells, Cultured
Gene Knockdown Techniques
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins / analysis
Nerve Tissue Proteins / metabolism*
Neural Cell Adhesion Molecules / analysis
Neural Cell Adhesion Molecules / metabolism*
Neurons / chemistry
Neurons / metabolism*
Protein Transport / physiology
Rats
Rats, Long-Evans
Receptors, AMPA / analysis
Receptors, AMPA / metabolism*
Receptors, Cell Surface / analysis
Receptors, Cell Surface / physiology*

Substances

Calcium-Binding Proteins
Nerve Tissue Proteins
Neural Cell Adhesion Molecules
Nrxn1 protein, mouse
Receptors, AMPA
Receptors, Cell Surface
SORCS1 protein, mouse
neurexin 3, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding