Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders

Nat Neurosci. 2017 Aug;20(8):1150-1161. doi: 10.1038/nn.4594.

Jing Li ¹, Wangshu Zhang ², Hui Yang ¹, Daniel P Howrigan ³ ⁴, Brent Wilkinson ¹, Tade Souaiaia ¹, Oleg V Evgrafov ¹ ⁵, Giulio Genovese ⁴ ⁶ ⁷, Veronica A Clementel ¹, Jennifer C Tudor ⁸, Ted Abel ⁹, James A Knowles ¹ ⁵, Benjamin M Neale ³ ⁴ ⁶, Kai Wang ¹ ⁵ ¹⁰, Fengzhu Sun ², Marcelo P Coba ¹ ⁵

Affiliations

1 Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA.
2 Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, USA.
3 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
4 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
5 Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
6 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
7 Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
8 Department of Biology, Saint Joseph's University, Philadelphia, Pennsylvania, USA.
9 Department of Molecular Physiology and Biophysics, Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa, USA.
10 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, USA.

PMID: 28671696 DOI: 10.1038/nn.4594

Abstract

The postsynaptic density (PSD) contains a collection of scaffold proteins used for assembling synaptic signaling complexes. However, it is not known how the core-scaffold machinery associates in protein-interaction networks or how proteins encoded by genes involved in complex brain disorders are distributed through spatiotemporal protein complexes. Here using immunopurification, proteomics and bioinformatics, we isolated 2,876 proteins across 41 in vivo interactomes and determined their protein domain composition, correlation to gene expression levels and developmental integration to the PSD. We defined clusters for enrichment of schizophrenia, autism spectrum disorders, developmental delay and intellectual disability risk factors at embryonic day 14 and adult PSD in mice. Mutations in highly connected nodes alter protein-protein interactions modulating macromolecular complexes enriched in disease risk candidates. These results were integrated into a software platform, Synaptic Protein/Pathways Resource (SyPPRes), enabling the prioritization of disease risk factors and their placement within synaptic protein interaction networks.

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