The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors.
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.
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.
Jeffrey N
JN
Savas
VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Luís F
LF
Ribeiro
VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Keimpe D
KD
Wierda
Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Rebecca
R
Wright
Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Laura A
LA
DeNardo-Wilke
VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Heather C
HC
Rice
UMR 5297, Interdisciplinary Institute for Neuroscience, University of Bordeaux and Centre National de la Recherche Scientifique, 33000 Bordeaux, France.
Ingrid
I
Chamma
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Yi-Zhi
YZ
Wang
School of Medicine, New York University, New York, New York 10016, USA.
Roland
R
Zemla
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Mathieu
M
Lavallée-Adam
VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Kristel M
KM
Vennekens
Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Matthew L
ML
O'Sullivan
Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Joseph K
JK
Antonios
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Elizabeth A
EA
Hall
UMR 5297, Interdisciplinary Institute for Neuroscience, University of Bordeaux and Centre National de la Recherche Scientifique, 33000 Bordeaux, France.
Olivier
O
Thoumine
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Alan D
AD
Attie
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: jyates@scripps.edu.
John R
JR
Yates
Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA; Neuroscience Discovery, F. Hoffman-La Roche, 4070 Basel, Switzerland.
Anirvan
A
Ghosh
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.
Joris
J
de Wit
D000818:Animals; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000032:analysis / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000032:analysis / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000032:analysis / Q000502:physiology*
D002135:Calcium-Binding Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D018091:Receptors, AMPA; D011956:Receptors, Cell Surface; C000595029:SORCS1 protein, mouse; C583456:neurexin 3, mouse