title: Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders.
abstract: The prevalence of autism spectrum disorders (ASDs) is rapidly growing, yet its molecular basis is poorly understood. We used a systems approach in which ASD candidate genes were mapped onto the ubiquitous human protein complexes and the resulting complexes were characterized. The studies revealed the role of histone deacetylases (HDAC1/2) in regulating the expression of ASD orthologs in the embryonic mouse brain. Proteome-wide screens for the co-complexed subunits with HDAC1 and six other key ASD proteins in neuronal cells revealed a protein interaction network, which displayed preferential expression in fetal brain development, exhibited increased deleterious mutations in ASD cases, and were strongly regulated by FMRP and MECP2 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 systems framework for analyzing complex human diseases.
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford, California, 94305 USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford, California, 94305 USA.
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford, California, 94305 USA.
authors.forename: Minyi
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan S4S 0A2, Canada.
authors.forename: Ramy H
authors.initials: RH
authors.lastname: Malty
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan S4S 0A2, Canada.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan S4S 0A2, Canada.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Minic
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan S4S 0A2, Canada.
authors.forename: Sadhna
authors.initials: S
authors.lastname: Phanse
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan S4S 0A2, Canada; Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Ke
authors.initials: K
authors.lastname: Jin
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, 94305 USA; Department of Pediatrics, Stanford, California, 94305 USA.
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Wall
authors.affiliation: Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Zhaolei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford, California, 94305 USA; Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, 94305 USA.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Urban
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, 94305 USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hallmayer
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan S4S 0A2, Canada.
authors.forename: Mohan
authors.initials: M
authors.lastname: Babu
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford, California, 94305 USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder