Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia

Abstract

Disrupted in Schizophrenia 1 (DISC1) is a schizophrenia risk gene associated with cognitive deficits in both schizophrenics and the normal ageing population. In this study, we have generated a network of protein-protein interactions (PPIs) around DISC1. This has been achieved by utilising iterative yeast-two hybrid (Y2H) screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and provides a molecular framework to explore the function of DISC1. The network implicates DISC1 in processes of cytoskeletal stability and organisation, intracellular transport and cellcycle/division. In particular, DISC1 looks to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Utilising a similar approach with dysbindin (DTNBP1), a second schizophrenia risk gene, we show that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

“…34,57 The experiments showed a significant decrease in the protein levels of LIS1, an interacting protein that forms a molecular complex with DISC1 and NUDEL and is involved in neuronal development. 24,26,28 The decrease in LIS1 expression in our mouse model is similar to a recent observation in our PC12 cell stable model of inducible expression, 57 indicating that the similar mechanisms of mutant hDISC1 action may occur in cell and mouse models. Another intriguing aspect of decreased levels of LIS1 in transgenic mice is its similarity to the reduced expression of LIS1 in the brain tissue from patients with schizophrenia.…”

“…21,23 Since the mutant protein associates with full-length DISC1, the cellular effects of the mutant DISC1 have been proposed to be mediated via dominant-negative mechanisms. 24,34 For example, mutant DISC1 disrupts formation of the DISC1-NUDEL-LIS1 protein complex, leading to abnormalities in neuronal migration, decreased complexity of dendrite arbors and neurite outgrowth, reminiscent of the findings from postmortem schizophrenia brain samples. [35][36][37] Importantly, the effects of mutant DISC1 have been demonstrated to be similar to those observed after suppression of endogenous DISC1 with RNAi that mimics haploinsufficiency.…”

“…[18][19][20] DISC1 protein likely acts as a scaffold protein, with multiple motifs mediating binding to several proteins and facilitating formation of protein complexes. [21][22][23][24] The DISC1 protein interactors include microtubule-interacting protein associated with tumor necrosis factor receptor associated factor-3, microtubule-associated protein 1A, 23 fasciculation and elongation protein zeta-1 25 and NudE-like (NUDEL) protein. 21,23 DISC1 has been suggested to exist in a neurodevelopmentally regulated protein complex with NUDEL and LIS1.…”

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

“…Most, if not all, promising candidate genes identified for schizophrenia in recent years had similar inconsistencies. [48][49][50][51][52][53] While it is possible that our findings are a false-positive, we believe that it is not very likely for several reasons. First, we performed false-positive rate evaluations with the Q-value method.…”

Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity

“…Ndel1 was shown to be the major ligand of Disc1, a familial genetic liability gene for major psychiatric disorders (Brandon et al, 2004;Camargo et al, 2007). Disc1/Ndel1 interaction regulates neuronal morphogenesis and positioning during neuronal integration (Duan et al, 2007).…”