Disrupted-In-Schizophrenia-1 (DISC1) is one of the most promising common susceptibility factors for major mental illnesses, such as schizophrenia and mood disorders. Our long-term goals are to clarify disease pathway(s) that commonly exist in major mental illnesses, especially schizophrenia. DISC1 appears to be a promising lead to advance analysis of the pathway(s). DISC1 protein is multifunctional with several distinct subcellular distributions, including the centrosome during neurodevelopment, the postsynaptic density, and the nucleus. Previous studies of autopsied brains and cell biology from our and other groups have suggested that DISC1 may have a regulatory role in gene transcription, which may be disturbed in major mental disorders. Thus, we hypothesize that study of a """"""""nuclear"""""""" pathway of DISC1 may elucidate the pathophysiology of major mental illnesses.
In Aim 1, we will determine biochemical mechanisms that regulate nuclear distribution of DISC1, focusing in particular on cis- elements and phosphorylation.
In Aim 2, we plan to characterize protein interactions of DISC1 in the nucleus, focusing on ATF4/CREB2 (a transcription factor), N-CoR (a nuclear co-repressor), and PML (the main component of the nuclear body). We hypothesize that DISC1 functions as a scaffold at the nuclear body to recruit components of activator/repressor complex to CREB/ATF transcriptional machinery.
Aim 3 is designed to elucidate mechanisms of how nuclear DISC1 regulates gene transcription, in particular CRE-mediated gene transcription. We hypothesize that possible recruitment of components of activator/repressor complex by DISC1 at the PML-nuclear body regulate CRE-mediated gene transcription at least via ATF4/CREB2. We hope that this mechanistic study will provide insight into understanding major mental illnesses and eventually lead to better therapeutic strategies for the diseases.

Public Health Relevance

Disrupted-In-Schizophrenia-1 (DISC1) is one of the most promising common susceptibility factors for major mental illnesses, such as schizophrenia and mood disorders. Because several lines of evidence have suggested """"""""nuclear"""""""" DISC1 may be involved in the pathophysiology of the diseases, we will study basic mechanism and regulation for """"""""nuclear"""""""" DISC1. We will particularly focus on the key mechanisms that regulates nuclear functions of DISC1, including cis-elements for nuclear targeting, phosphorylation, SUMOylation, and protein interaction with other nuclear proteins, as well as its function in gene transcription.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH069853-08
Application #
8050163
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (90))
Program Officer
Meinecke, Douglas L
Project Start
2003-12-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
8
Fiscal Year
2011
Total Cost
$365,310
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sumitomo, Akiko; Yukitake, Hiroshi; Hirai, Kazuko et al. (2018) Ulk2 controls cortical excitatory-inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons. Hum Mol Genet 27:3165-3176
Posporelis, Sotirios; Coughlin, Jennifer M; Marsman, Anouk et al. (2018) Decoupling of Brain Temperature and Glutamate in Recent Onset of Schizophrenia: A 7T Proton Magnetic Resonance Spectroscopy Study. Biol Psychiatry Cogn Neurosci Neuroimaging 3:248-254
Tanaka, Motomasa; Ishizuka, Koko; Nekooki-Machida, Yoko et al. (2017) Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease. J Clin Invest 127:1438-1450
Shao, Lisha; Lu, Binyan; Wen, Zhexing et al. (2017) Disrupted-in-Schizophrenia-1 (DISC1) protein disturbs neural function in multiple disease-risk pathways. Hum Mol Genet 26:2634-2648
Nucifora, L G; Tanaka, T; Hayes, L N et al. (2017) Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry. Transl Psychiatry 7:e1215
Pandey, Himani; Bourahmoune, Katia; Honda, Takato et al. (2017) Genetic interaction of DISC1 and Neurexin in the development of fruit fly glutamatergic synapses. NPJ Schizophr 3:39
Kondo, Mari A; Fukudome, Daisuke; Smith, Dani R et al. (2016) Dimensional assessment of behavioral changes in the cuprizone short-term exposure model for psychosis. Neurosci Res 107:70-74
Tomoda, T; Sumitomo, A; Jaaro-Peled, H et al. (2016) Utility and validity of DISC1 mouse models in biological psychiatry. Neuroscience 321:99-107
Cash-Padgett, Tyler; Sawa, Akira; Jaaro-Peled, Hanna (2016) Increased stereotypy in conditional Cxcr4 knockout mice. Neurosci Res 105:75-9
Kim, Sun-Hong; Shahani, Neelam; Bae, Byoung-Ii et al. (2016) Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53. Hum Mol Genet 25:2514-2524

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