Discovered over a decade ago by scientists studying a Scottish family riddled with mental disorders, variations in the gene DISC1, or "discovered in schizophrenia-1", have been heavily linked to development of schizophrenia and, to a lesser extent, bipolar disorder. Only recently, however, have scientists begun unraveling the importance of the gene and its mechanistic functions. DISC1 encodes a scaffolding protein, a protein whose function is to help organize signaling pathways via formation of complexes with multiple other proteins in a way that allows them to interact. Experiments have shown the critical importance of DISC1 in a multitude of developmental functions, including neuronal migration, axonal and dendritic growth, and synaptogenesis, and neurogenesis, to name a few. Of the half-dozen or so DISC1-dependent signaling pathways discovered, a recent paper shows that disruptions in the Wnt pathway is implicated in a significant amount of the abnormal neurological features seen in persons with schizophrenia (and bipolar).
The Wnt pathway is critical for cell proliferation during development and plays key roles in embryogeneis, neuronal growth, and certain types of cancer. Activation of this pathway results in an increase of B-catenin, which associates with other proteins to upregulate transcription of certain genes necessary for proper neuronal development. Recent experiments have showed that schizophrenics and bipolar patients with genetic variations of the DISC1 gene show inhibited Wnt signaling and reduced neuroblastoma (N2a) cell proliferation. These studies also showed that the most common DISC1 variants had a decreased affinity for the protein GSK3-B, an intermediate in the Wnt pathway, to which it normally binds and inhibits. GSK3-B is responsible for the phosphorylation and subsequent degradation of B-catenin in the absence of Wnt signaling, and it is thought that in the absence of Wnt DISC1 is responsible for its inhibition. Since schizophrenic variations of DISC1 show a decreased affinity for GSK3-B, this may suggest a mechanism for the reduced signaling seen in many areas of the schizophrenic brain.
So why does any of this matter? Drug treatments. Lithium, the classic mood-stabilizing drug used to treat mania, was shown to inhibit GSK3-B just a little over a decade ago, and its mechanism of action is only now coming to light. Some antipsychotics have also been shown to indirectly stimulate the Wnt pathway, which might be a significant aspect of their pharmacological actions. With this knowledge in hand, selective inhibitors of GSK3-B (mimicking the actions of DISC1) or agonists for Frizzled, the Wnt receptor, could effectively attenuate many of the symptoms associated with schizophrenia and bipolar disorder. Along with brain imaging and genetic testing, disruptions in this pathway could also serve as an early marker for children predisposed for these mental disorders. Drugs such as those mentioned above could also prove useful in children with a high risk for developing schizophrenia or bipolar, in which an early drug regiment could blunt the onset of the disease and possibly prevent a lifelong struggle with a mental disorder. Although there are many other genes and pathways implicated in these cognitive disorders, the massive developmental impact of DISC1 variants and their effects on the Wnt pathway opens up promising new therapeutic opportunities for the treatment of schizophrenia and bipolar disorder.
Paper: "Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development", Singh et. al