title: Quantitative proteomic and genetic analyses of the schizophrenia susceptibility factor dysbindin identify novel roles of the biogenesis of lysosome-related organelles complex 1.
abstract: The Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1) is a protein complex containing the schizophrenia susceptibility factor dysbindin, which is encoded by the gene DTNBP1. However, mechanisms engaged by dysbindin defining schizophrenia susceptibility pathways have not been quantitatively elucidated. Here, we discovered prevalent and novel cellular roles of the BLOC-1 complex in neuronal cells by performing large-scale Stable Isotopic Labeling of Cells in Culture (SILAC) quantitative proteomics combined with genetic analyses in dysbindin-null mice (Mus musculus) and the genome of schizophrenia patients. We identified 24 proteins that associate with the BLOC-1 complex, many of which were altered in content/distribution in cells or tissues deficient in BLOC-1. New findings include BLOC-1 interactions with the COG complex, a Golgi apparatus tether, and antioxidant enzymes peroxiredoxins 1-2. Importantly, loci encoding eight of the 24 proteins are affected by genomic copy number variation in schizophrenia patients. Thus, our quantitative proteomic studies expand the functional repertoire of the BLOC-1 complex and provide insight into putative molecular pathways of schizophrenia susceptibility.
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Avanti
authors.initials: A
authors.lastname: Gokhale
authors.forename: Jennifer
authors.initials: J
authors.lastname: Larimore
authors.forename: Erica
authors.initials: E
authors.lastname: Werner
authors.forename: Lomon
authors.initials: L
authors.lastname: So
authors.forename: Andres
authors.initials: A
authors.lastname: Moreno-De-Luca
authors.forename: Christa
authors.initials: C
authors.lastname: Lese-Martin
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Lupashin
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.forename: Victor
authors.initials: V
authors.lastname: Faundez
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D040901:Proteomics / Q000379:methods*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C104378:BLOC1S1 protein, human; D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D009419:Nerve Tissue Proteins