Schizo and other maladies.

StacyMoran at Eureka: “Recent studies have identified common genetic mutations conferring modest risk and rare variants comprising significant risk. One example of a rare cause of psychiatric disorders is the Disrupted in Schizophrenia-1 (DISC1) gene, first identified in a large Scottish pedigree displaying schizophrenia, bipolar disorder and depression.” 

The paper:

Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development. Karun K. Singh, Gianluca De Rienzo, Laurel Drane, Yingwei Mao, Zachary Flood, Jon Madison, Manuel Ferreira, Sarah Bergen, Cillian King, Pamela Sklar, Hazel Sive, Li-Huei Tsai. Neuron 72: 545. Nov 17. 2011.

 “Wnt Signaling, DISC1, and Psychiatric Disorders: Our current and previous work (Mao et al., 2009) suggest a prominent role for DISC1 in regulating the Wnt signaling pathway during brain development. Given that our data suggest that specific human DISC1 variants affect Wnt signaling and brain development, this pathway may indeed play a significant role in psychiatric disorders. This is particularly interesting given that a common mood stabilizer, lithium, is a known GSK3β inhibitor ( [Beaulieu et al., 2008] and [Harwood, 2005] ) and can directly activate Wnt-TCF/LEF gene transcription (Stambolic et al., 1996). Furthermore, some of the recently identified genetic susceptibility factors also fall within the Wnt signaling pathway, directly and indirectly. For example, the Akt gene, which can directly regulate GSK3β activity and downstream TCF/LEF signaling, is itself a schizophrenia risk gene and has been shown to be downregulated in postmortem brains of schizophrenia patients (Emamian et al., 2004). In addition, one of the critical-domain genes in the

despair of not belonging

schizophrenia risk-associated 1q21.1 copy number variation (CNV) is B cell lymphoma 9 (Bcl9), which is required for shuttling and keeping β-catenin within the nucleus in response to Wnt stimulation ( [Consortium, 2008] , [Kramps et al., 2002] and [Stefansson et al., 2008] ). Interestingly, a recent study from the Nestler laboratory has shown that Wnt/GSK3β signaling is important in a mouse model of depression (Wilkinson et al., 2011). This collective data suggest that Wnt/GSK3β signaling is important in mediating mood and psychiatric disorders and may represent at least one pathogenic signaling pathway. In conclusion, our data demonstrate that rare and common DISC1 variants impact Wnt signaling in different model systems to ultimately impair brain development. These data provide a framework from which to explain previously reported associations between common DISC1 variants and human brain structural changes and psychiatric phenotypes. Given that future studies will begin to provide sequencing data for genes that regulate Wnt signaling and brain development, it will be critical to understand how DISC1 variants interact with these genes and how these interactions influence risk for psychiatric disorders.”

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