synaptic interactome mining reveals p140cap as a new hub for psd proteins involved in psychiatric and neurological disorders

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2017
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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.
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alfieri2017frontierssynaptic Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Annalisa Alfieri;Oksana Sorokina;Annie Adrait;Annie Adrait;Annie Adrait;Costanza Angelini;Isabella Russo;Alessandro Morellato;Michela Matteoli;Michela Matteoli;Elisabetta Menna;Elisabetta Menna;Elisabetta Boeri Erba;Elisabetta Boeri Erba;Elisabetta Boeri Erba;Colin McLean;J. Douglas Armstrong;Ugo Ala;Ugo Ala;Joseph D. Buxbaum;Joseph D. Buxbaum;Joseph D. Buxbaum;Joseph D. Buxbaum;Joseph D. Buxbaum;Joseph D. Buxbaum;Alfredo Brusco;Alfredo Brusco;Yohann Couté;Yohann Couté;Yohann Couté;Silvia De Rubeis;Silvia De Rubeis;Emilia Turco;Paola Defilippi
Journal international journal of nanomedicine
Year 2017
DOI
10.3389/fnmol.2017.00212
URL
http://journal.frontiersin.org/article/10.3389/fnmol.2017.00212/full
Keywords
schizophrenia synaptic plasticity synaptic transmission neuropsychiatry biological psychiatry autismneurosciences

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