title: Convergence of two independent mental disease genes on the protein level: recruitment of dysbindin to cell-invasive disrupted-in-schizophrenia 1 aggresomes.
abstract: BACKGROUND
  Both disrupted-in-schizophrenia 1 (DISC1) and dysbindin have been identified as schizophrenia candidate genes in independent genetic linkage studies. The proteins have been assigned distinct subcellular locations and functions. We investigated whether both proteins converge into a common pathway specific for schizophrenia or mental diseases.
  
  
  METHODS
  DISC1 and dysbindin were expressed as recombinant proteins with or without a fluorescent protein-tag in human or mouse neuroblastoma cells and as recombinant proteins in E. coli. Postmortem brains of patients with mental diseases from the Stanley Research Medical Institute's Consortium Collection were used to demonstrate molecular interactions in biochemically purified protein fractions.
  
  
  RESULTS
  First, upon overexpression in neuroblastoma cells, DISC1 formed aggresomes that recruited homologous soluble C-terminal DISC1 fragment or heterologous dysbindin. Domains involved in binding could be mapped to DISC1 (316-597) and dysbindin (82-173), indicating a specific interaction. In addition, recruitment was demonstrated when externally added, purified DISC1 aggresomes penetrated recipient cells after coincubation. Second, a direct interaction between soluble DISC1 protein and dysbindin was demonstrated in a cell free system using E. coli-expressed proteins. Third, co-aggregation of DISC1 and dysbindin was demonstrated in postmortem brains for a subgroup of cases with chronic mental disease but not healthy control subjects.
  
  
  CONCLUSIONS
  A direct interaction of soluble and insoluble DISC1 protein with dysbindin protein demonstrates convergence of so far considered independent mental disease genes by direct molecular interaction. Our findings highlight protein aggregation and recruitment as a biological mechanism in mental disease.
authors.affiliation: Department of Neuropathology, Heinrich Heine University Medical School, Düsseldorf, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ottis
authors.forename: Verian
authors.initials: V
authors.lastname: Bader
authors.forename: Svenja V
authors.initials: SV
authors.lastname: Trossbach
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.forename: Max
authors.initials: M
authors.lastname: Michel
authors.forename: S Rutger
authors.initials: SR
authors.lastname: Leliveld
authors.forename: Carsten
authors.initials: C
authors.lastname: Korth
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002461:Cell Line, Transformed; D057846:Cell-Penetrating Peptides / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D001523:Mental Disorders / Q000378:metabolism*; D051379:Mice; D057054:Molecular Imaging / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; C412476:DISC1 protein, human; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D009419:Nerve Tissue Proteins