Psychiatric genetics has turned a corner—increasingly robust findings can be placed in a neurobiological context, with practical implications for understanding disease pathogenesis and developing of therapeutics. A milestone in this effort was the discovery of the DISC1 (disrupted in Schizophrenia 1) gene, found via analysis of a large Scottish family with a high rate of schizophrenia and psychotic affective disorder. All affected members of the family carry a (1;11)(q42.1; q14.3) translocation; the chromosome 1 translocation break point falls between exon 8 and 9 of DISC1, presumably resulting in loss of DISC1 expression. This finding has launched an entire subfield of schizophrenia genetics and neurobiology, with an emphasis on the role of the DISC1 gene product and its protein interaction partners in neurodevelopment and synaptic function (Chubb et al, 2008).
In the past year, DISC1 has been put into the context of key signal transduction pathways and other genetic findings. In one critical study (Mao et al, 2009), DISC1 was shown to modulate the ‘canonical’ Wnt-signaling pathway. This pathway (Komiya and Habas, 2008) is activated when a member of the Wnt family of secreted glycoproteins binds a member of the Frizzled receptor family along with coreceptors. Pathway activation reduces GSK3β kinase activity, resulting in diminished phosphorylation of β-catenin. Unphosphorylated β-catenin accumulates in the cytoplasm and is translocated into the nucleus, where it functions as a transcriptional coactivator. Among other effects, this transcriptional activity can drive neuronal neurogenesis. DISC1 directly interacts with GSK3β, inhibiting GSK3β phosphorylation of β-catenin and thus increasing β-catenin-induced transcriptional activity. The effect is to mimic Wnt pathway activation. Loss of DISC1 inhibits β-catenin-induced transcription, providing a potential mechanism by which DISC1 loss of function mutations might exert their effect.
DISC1 has also been linked to pathways involving Neuregulin-1 (NRG1), one of the most robust candidate genes for schizophrenia (Mei and Xiong 2008). Extracellular NRG1, cleaved from Pro-NRG1, interacts with and activates the ErbB family of receptor protein kinases (ErbB2, 3, 4, and EGFR), starting a cascade that activates a number of partially overlapping pathways, including Raf—MEK–ERK and PI3K–Akt. NRG1 signaling has been implicated in neuronal migration, axon guidance, synapse formation, myelination, and oligodendrocyte development. NRG-1 activated Akt inhibits GSK3β, tying NRG1 signaling to Wnt and DISC1 activity. The related effects of DISC1 and NRG1 have been highlighted in a zebrafish model, in which DISC1 loss produced developmental deficits very similar to loss of NRG1 signaling, including failure of normal oligodendrocyte development and near total failure of olig2-positive cerebellar neuron development (Wood et al, 2009). The effect of psychotropic agents on these pathways provides an additional link to major mental illness. For instance, lithium activates Akt and inhibits GSK3β, whereas antipsychotic agents, by antagonism of D2 receptors, block the stimulatory effect of dopamine on Akt.
Overall, the convergence of genetic, pharmacological, and neurobiological data have opened the door to multiple novel potential therapeutic targets in the DISC1–Wnt–NRG1 systems, and this neurogenetic approach holds considerable promise for future research. For instance, the recent association of the MHC locus on chromosome 6p with schizophrenia (e.g., Stefansson et al, 2009) supports the long standing concept that environmental factors such as infection may have a role in schizophrenia, and provides a rationale for models of disease that encompass both genetic and environmental factors. Associations of neurogranin on 11q24.2 and transcription factor 4 (TCF4) on 18q21.2 with schizophrenia (Stefansson et al, 2009) may lead to new pathways with additional therapeutic targets. Psychiatric research has entered an era in which genetic findings implicate specific signaling pathways, leading to new insights into disease pathogenesis and the development of new approaches to therapeutics.
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Potential conflicts of interest for RLM: Consultant for AstraZeneca, grant support from Medivation, Amarin, Pfizer, and Forest Pharmaceuticals. No conflicts of interest for CAR.
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Margolis, R., Ross, C. Neuronal signaling pathways: genetic insights into the pathophysiology of major mental illness. Neuropsychopharmacol 35, 350–351 (2010). https://doi.org/10.1038/npp.2009.137
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