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Front Mol Neurosci. 2017 Jun 30;10:212. doi: 10.3389/fnmol.2017.00212. eCollection 2017.

Synaptic Interactome Mining Reveals p140Cap as a New Hub for PSD Proteins Involved in Psychiatric and Neurological Disorders.

Author information

1
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, Università di TorinoTorino, Italy.
2
The Institute for Adaptive and Neural Computation, School of Informatics, University of EdinburghEdinburgh, United Kingdom.
3
Université Grenoble Alpes, iRTSV-BGEGrenoble, France.
4
CEA, iRTSV-BGEGrenoble, France.
5
Institut National de la Santé et de la Recherche Médicale, BGEGrenoble, France.
6
Institute of Neuroscience, Consiglio Nazionale delle Ricerche (CNR)Milan, Italy.
7
Humanitas Clinical and Research Center, IRCCSRozzano, Italy.
8
Institut de Biologie Structurale, Université Grenoble AlpesGrenoble, France.
9
CEA, DSV, IBSGrenoble, France.
10
Centre National de la Recherche Scientifique, IBSGrenoble, France.
11
GenoBiToUS-Genomics and Bioinformatics, Università di TorinoTurin, Italy.
12
Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount SinaiNew York, NY, United States.
13
Department of Psychiatry, Icahn School of Medicine at Mount SinaiNew York, NY, United States.
14
Department of Neuroscience, Icahn School of Medicine at Mount SinaiNew York, NY, United States.
15
Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew York, NY, United States.
16
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiNew York, NY, United States.
17
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount SinaiNew York, NY, United States.
18
Department of Medical Sciences, Università di TorinoTurin, Italy.
19
Medical Genetics Unit, Azienda Ospedaliera Città della Salute e della Scienza di TorinoTurin, Italy.

Abstract

Altered synaptic function has been associated with neurological and psychiatric conditions including intellectual disability, schizophrenia and autism spectrum disorder (ASD). Amongst the recently discovered synaptic proteins is p140Cap, an adaptor that localizes at dendritic spines and regulates their maturation and physiology. We recently showed that p140Cap knockout mice have cognitive deficits, impaired long-term potentiation (LTP) and long-term depression (LTD), and immature, filopodia-like dendritic spines. Only a few p140Cap interacting proteins have been identified in the brain and the molecular complexes and pathways underlying p140Cap synaptic function are largely unknown. Here, we isolated and characterized the p140Cap synaptic interactome by co-immunoprecipitation from crude mouse synaptosomes, followed by mass spectrometry-based proteomics. We identified 351 p140Cap interactors and found that they cluster to sub complexes mostly located in the postsynaptic density (PSD). p140Cap interactors converge on key synaptic processes, including transmission across chemical synapses, actin cytoskeleton remodeling and cell-cell junction organization. Gene co-expression data further support convergent functions: the p140Cap interactors are tightly co-expressed with each other and with p140Cap. Importantly, the p140Cap interactome and its co-expression network show strong enrichment in genes associated with schizophrenia, autism, bipolar disorder, intellectual disability and epilepsy, supporting synaptic dysfunction as a shared biological feature in brain diseases. Overall, our data provide novel insights into the molecular organization of the synapse and indicate that p140Cap acts as a hub for postsynaptic complexes relevant to psychiatric and neurological disorders.

KEYWORDS:

autism; epilepsy; intellectual disability; p140Cap; postsynaptic density; schizophrenia; synaptic plasticity; synaptic transmission

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