Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders

Abstract

SummaryThe prevalence of autism spectrum disorders (ASDs) is rapidly growing, yet its molecular basis is poorly understood. Here, we sought to gain a systems-level understanding of ASD candidate genes by mapping them onto ubiquitous human protein complexes and characterizing the resulting complexes. These studies revealed the role of histone deacetylases (HDAC1/2) in regulating the expression of ASD orthologs in the embryonic mouse brain. Next, proteome-wide screens for subunits co-complexed with HDAC1 and six other key ASD proteins in human neuronal cells revealed a protein interaction network that displayed preferential expression in fetal brain development, exhibited increased deleterious mutations in ASD cases, and encompassed genes strongly regulated by FMRP and MECP2, mutations that are causal for fragile X and Rett syndromes, respectively. Overall, our study reveals molecular components in ASD, suggests a shared mechanism between the syndromic and idiopathic forms of ASDs, and provides a groundwork for analyzing complex human diseases