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- Title
Synaptic Interactome Mining Reveals p140Cap as a New Hub for PSD Proteins Involved in Psychiatric and Neurological Disorders.
- Authors
Alfieri, Annalisa; Sorokina, Oksana; Adrait, Annie; Angelini, Costanza; Russo, Isabella; Morellato, Alessandro; Matteoli, Michela; Menna, Elisabetta; Erba, Elisabetta Boeri; McLean, Colin; Armstrong, J. Douglas; Ala, Ugo; Buxbaum, Joseph D.; Brusco, Alfredo; Couté, Yohann; De Rubeis, Silvia; Turco, Emilia; Defilippi, Paola
- 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 knockoutmice 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.
- Subjects
NEUROLOGICAL disorders; AUTISM spectrum disorders
- Publication
Frontiers in Molecular Neuroscience, 2017, p1
- ISSN
1662-5099
- Publication type
Article
- DOI
10.3389/fnmol.2017.00212