Disrupted-in-Schizophrenia-1 expression is regulated by -site amyloid precursor protein cleaving enzyme-1-neuregulin cascade

Departments of Psychiatry, Neuroscience, and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2010; 107(12):5622-7. DOI: 10.1073/pnas.0909284107
Source: PubMed


Neuregulin-1 (NRG1) and Disrupted-in-Schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ErbB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia.

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Available from: Amelia Stanco
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    • "Conformational diseases [1] are primarily caused by the misfolding of disease-related proteins. Although prion diseases [2] are known to be caused by the conformational conversion of a prion protein [3] , conformational instabilities resulting in oligomer formation are regarded as the major causes of other neurodegenerative diseases [4] (e.g., Alzheimer's disease [5], Parkinson's disease [6], and amyotrophic lateral sclerosis [7] ), certain psychiatric diseases (e.g., schizophrenia [8] ), diabetes mellitus (i.e., type-II dia- betes) [9], and several cancers involving p53 mutation [10]. Medical chaperones (MCs) [11,12] specifically bind to and stabilize the native conformation of relevant proteins and prevent abnormal aggregate formation. "
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    ABSTRACT: To accelerate the logical drug design procedure, we created the program "NAGARA," a plugin for PyMOL, and applied it to the discovery of small compounds called medical chaperones (MCs) that stabilize the cellular form of a prion protein (PrP(C)). In NAGARA, we constructed a single platform to unify the docking simulation (DS), free energy calculation by molecular dynamics (MD) simulation, and interfragment interaction energy (IFIE) calculation by quantum chemistry (QC) calculation. NAGARA also enables large-scale parallel computing via a convenient graphical user interface. Here, we demonstrated its performance and its broad applicability from drug discovery to lead optimization with full compatibility with various experimental methods including Western blotting (WB) analysis, surface plasmon resonance (SPR), and nuclear magnetic resonance (NMR) measurements. Combining DS and WB, we discovered anti-prion activities for two compounds and tegobuvir (TGV), a non-nucleoside non-structural protein NS5B polymerase inhibitor showing activity against hepatitis C virus genotype 1. Binding profiles predicted by MD and QC are consistent with those obtained by SPR and NMR. Free energy analyses showed that these compounds stabilize the PrP(C) conformation by decreasing the conformational fluctuation of the PrP(C). Because TGV has been already approved as a medicine, its extension to prion diseases is straightforward. Finally, we evaluated the affinities of the fragmented regions of TGV using QC and found a clue for its further optimization. By repeating WB, MD, and QC recursively, we were able to obtain the optimum lead structure.
    Full-text · Article · Jan 2016 · Biochemical and Biophysical Research Communications
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    • "The studies from the Sive and Morris laboratories showed roles for disc1 in embryonic neurogenesis and neural crest migration/differentiation respectively, while our studies revealed a novel requirement for disc1 in the specification of oligodendrocyte precursor cells in the hindbrain (Wood et al., 2009). Subsequent studies have supported an important role for DISC1 in oligodendrocyte development in higher vertebrates (Hattori et al., 2014; Katsel et al., 2011; Seshadri et al., 2010; Shimizu et al., 2014), while interrogation of a CNS cell types exon array (Cahoy et al., 2008) by us revealed that among the CNS cell types analysed, Disc1 was most highly expressed in OPCs. DISC1 has also been implicated in agenesis of the corpus callosum in humans (Osbun et al., 2011). "
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    ABSTRACT: DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most intensively studied genetic risk factors for mental illness since it was discovered through positional mapping of a translocation breakpoint in a large Scottish family where a balanced chromosomal translocation was found to segregate with schizophrenia and affective disorders. While the evidence for it being central to disease pathogenesis in the original Scottish family is compelling, recent genome-wide association studies have not found evidence for common variants at the DISC1 locus being associated with schizophrenia in the wider population. It may therefore be the case that DISC1 provides an indication of biological pathways that are central to mental health issues and functional studies have shown that it functions in multiple signalling pathways. However, there is little information regarding factors that function upstream of DISC1 to regulate its expression and function. We herein demonstrate that Sonic hedgehog (Shh) signalling promotes expression of disc1 in the zebrafish brain. Expression of disc1 is lost in smoothened mutants that have a complete loss of Shh signal transduction, and elevated in patched mutants which have constitutive activation of Shh signalling. We previously demonstrated that disc1 knockdown has a dramatic effect on the specification of oligodendrocyte precursor cells (OPC) in the hindbrain and Shh signalling is known to be essential for the specification of these cells. We show that disc1 is prominently expressed in olig2-positive midline progenitor cells that are absent in smo mutants, while cyclopamine treatment blocks disc1 expression in these cells and mimics the effect of disc1 knock down on OPC specification. Various features of a number of psychiatric conditions could potentially arise through aberrant Hedgehog signalling. We therefore suggest that altered Shh signalling may be an important neurodevelopmental factor in the pathobiology of mental illness.
    Full-text · Article · Sep 2015 · Biology Open
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    • "It can also be inferred from the high co-occurrence of WM-diseases, such as multiple sclerosis (MS), leukodystrophies, and velocardiofacial syndrome, with SZ-like psychoses that OLs and myelin dysfunction may play a key role in neuropsychiatric disease pathophysiology (Baumann et al., 2002; Kosmidis et al., 2010; Walterfang et al., 2005). Despite substantial evidence suggesting the role of OL abnormalities in the pathophysiology of neuropsychiatric diseases, neurobiological studies of these diseases have predominantly focused on neurons whereas only a few reports have studied OLs (Katsel et al., 2011; Seshadri et al., 2010; Wood et al., 2009). We have reported DISC1 binding zinc (DBZ) finger protein, also known as ZNF365 or Su48, is a novel Disrupted-in-schizophrenia 1 (DISC1) binding protein with a predicted C2H2-type zinc-finger motif and coiledcoil domains (Hattori et al., 2007). "
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    ABSTRACT: Recent studies have shown changes in myelin genes and alterations in white matter structure in a wide range of psychiatric disorders. Here we report that DBZ, a central nervous system (CNS)-specific member of the DISC1 interactome, positively regulates the oligodendrocyte (OL) differentiation in vivo and in vitro. In mouse corpus callosum (CC), DBZ mRNA is expressed in OL lineage cells and expression of DBZ protein peaked before MBP expression. In the CC of DBZ-KO mice, we observed delayed myelination during the early postnatal period. Although the myelination delay was mostly recovered by adulthood, OLs with immature structural features were more abundant in adult DBZ-KO mice than in control mice. DBZ was also transiently upregulated during rat OL differentiation in vitro before myelin marker expression. DBZ knockdown by RNA interference resulted in a decreased expression of myelin-related markers and a low number of cells with mature characteristics, but with no effect on the proliferation of oligodendrocyte precursor cells. We also show that the expression levels of transcription factors having a negative-regulatory role in OL differentiation were upregulated when endogenous DBZ was knocked down. These results strongly indicate that OL differentiation in rodents is regulated by DBZ. GLIA 2014.
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