Quantitative proteomic and genetic analyses of the schizophrenia susceptibility factor dysbindin identify novel roles of the biogenesis of lysosome-related organelles complex 1

J Neurosci. 2012 Mar 14;32(11):3697-711. doi: 10.1523/JNEUROSCI.5640-11.2012.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / physiology
  • Cell Line, Tumor
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Genetic Association Studies / methods*
  • Genetic Predisposition to Disease / genetics*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / physiology
  • Proteomics / methods*
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Schizophrenia / pathology

Substances

  • BLOC1S1 protein, human
  • Carrier Proteins
  • Dtnbp1 protein, mouse
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Nerve Tissue Proteins