title: Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site.
abstract: Disrupted in schizophrenia 1 (DISC1) has been identified as a putative risk factor for schizophrenia and affective disorders through study of a Scottish family with a balanced (1;11) (q42.1;q14.3) translocation, which results in the disruption of the DISC1 locus and cosegregates with major psychiatric disease. Several other reports of genetic linkage and association between DISC1 and schizophrenia in a range of patient populations have added credibility to the DISC1-schizophrenia theory, but the function of the DISC1 protein is still poorly understood. Recent studies have suggested that DISC1 plays a role in neuronal outgrowth, possibly through reported interactions with the molecules Nudel and FEZ1. Here we have analyzed the DISC1 protein sequence to identify previously unknown regions that are important for the correct targeting of the protein and conducted imaging studies to identify DISC1 subcellular location. We have identified a central coiled-coil region and show it is critical for the subcellular targeting of DISC1. This domain is independent from the C-terminal Nudel binding domain highlighting the multidomain nature/functionality of the DISC1 protein. Furthermore, we have been able to provide the first direct evidence that DISC1 is localized to mitochondria in cultured cortical neurons that are dependent on an intact cytoskeleton. Surprisingly, Nudel is seen to differentially associate with mitochondrial markers in comparison to DISC1. Disruption of the cytoskeleton results in colocalization of Nudel and mitochondrial markers-the first observation of such a direct relationship. Mitochondrial dysfunction has been implicated to play a role in schizophrenia so we speculate that mutations in DISC1 or Nudel may impair mitochondrial transport or function, initiating a cascade of events culminating in psychiatric illness.
authors.affiliation: Merck Sharp and Dohme Research Labs, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. nick_brandon@merck.com
authors.forename: N J
authors.initials: NJ
authors.lastname: Brandon
authors.forename: I
authors.initials: I
authors.lastname: Schurov
authors.forename: L M
authors.initials: LM
authors.lastname: Camargo
authors.forename: E J
authors.initials: EJ
authors.lastname: Handford
authors.forename: B
authors.initials: B
authors.lastname: Duran-Jimeniz
authors.forename: P
authors.initials: P
authors.lastname: Hunt
authors.forename: J K
authors.initials: JK
authors.lastname: Millar
authors.forename: D J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: M S
authors.initials: MS
authors.lastname: Shearman
authors.forename: P J
authors.initials: PJ
authors.lastname: Whiting
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; C421108:NDEL1 protein, human; D009419:Nerve Tissue Proteins