![]() ![]() ![]() (8) Furthermore, these mental-illness-related phenotypes are also treated in part by inhibitors of glycogen synthase kinase 3β (GSK3β), (9, 10) a DISC1 interacting protein whose other inhibitors include the potent mood stabilizer, lithium. (7) Additionally, depression and schizophrenia-related phenotypes seen in two mouse models of DISC1 mutation are partially restored by the antidepressant bupropion or the antipsychotics haloperidol and clozapine, respectively. The DISC1 protein interaction network therefore makes an attractive target for future therapeutic intervention, (6) and already some evidence shows DISC1 to be affected by known therapeutic drugs, with the atypical antipsychotics olanzapine and risperidone altering DISC1 transcript levels in the mouse brain. ![]() These predictions and priority areas can inform future research in the translational and potentially guide the therapeutic processes. We discuss signaling pathways of high pharmacological potential wherein DISC1 participates, including those involving phosphodiesterase 4 (PDE4) and glycogen synthase kinase 3 (GSK3). We review, analyze, and make predictions regarding the secondary structure and propensity for disordered regions within DISC1, its protein-interaction domains, subcellular localization motifs, and the structural and functional implications of common and ultrarare DISC1 variants associated with major mental illness. Here, we critically appraise the available bioinformatics and biochemical analyses on DISC1 and key interacting proteins, and integrate this with the genetic and biological data. By contrast, there is a relative deficit of structural information to relate to the myriad biological functions of DISC1. Disrupted in schizophrenia 1 (DISC1) is well established as a genetic risk factor across a spectrum of psychiatric disorders, a role supported by a growing body of biological studies, making the DISC1 protein interaction network an attractive therapeutic target.
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