Quantitative Proteomic and Genetic Analyses of the Schizophrenia Susceptibility Factor Dysbindin Identify Novel Roles of the BLOC-1 Complex

• Type of Material: Article
• Authors: Avanti S Gokhale, Emory University; Jennifer Lynn Larimore, Emory University; Erica Werner, Emory University; Lomon So, Emory University; Andres Moreno De Luca, Emory University; Christa Lese Martin, Emory University; Vladimir V. Lupashin, University of Arkansas; Yoland Smith, Emory University; Victor Faundez, Emory University
• Language: English
• Date: 2012-03-14
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 the authors
• Final Published Version (URL): http://www.jneurosci.org/content/32/11/3697
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 32
• Issue: 11
• Start Page: 3697
• End Page: 3711
• Grant/Funding Information: This work was supported in part by the Neuronal Imaging Core of the Emory Neuroscience National Institute of Neurological Disorders and Stroke Core Facilities Grant P30NS055077, and by the Flow Cytometry Core Facility of the Emory University School of Medicine.; A.G. and J.L. were supported by National Institutes of Health Fellowships in Research and Science Teaching Grant K12 GM000680.; This work was supported by grants from the National Institutes of Health to V.F. (NS42599, GM077569) and V.V.L. (GM083144).
• Research Categories: Biology, Neuroscience; Biology, Cell; Biology, Genetics

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 quantitative proteomics (SILAC) 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.