Abstract
The Disrupted in schizophrenia 1 (DISC1) gene encodes a scaffolding protein that is involved in many neural functions such as neurogenesis, neural differentiation, embryonic neuron migration and neurotransmitter signalling. DISC1 was originally implicated in schizophrenia in a single family with a drastic mutation, a chromosomal translocation severing the mid-point of the gene (aa 598). Some common DISC1 variants have also been associated with schizophrenia in the general population, but those located far from the chromosomal translocation breakpoint likely have a different functional impact. We previously reported that DISC1 forms a protein complex with dopamine D2 receptor (D2R), the main target for antipsychotic medications. The D2R-DISC1 complex is elevated in brain tissue from schizophrenia patients and facilitates glycogen synthase kinase (GSK)-3 signaling. The DISC1 R264Q variant is located within the region that binds the D2R, and we found that this polymorphism increases the affinity of DISC1 for the D2R and promotes GSK3 activity. Our results suggest a possible mechanism by which this common polymorphism could affect aspects of brain function that are relevant to psychosis and schizophrenia. This provides additional insight into molecular mechanisms underlying schizophrenia that could be exploited in the development of novel pharmacological treatments.
Highlights
Disrupted in schizophrenia 1 (DISC1) is an important susceptibility gene for many psychiatric disorders because it codes for a powerful regulatory protein with a large interacting network that regulates fundamental brain functions [1]
We focused on the R264Q DISC1 variant because the mutation is within the DISC1 region that interacts with D2 receptor (D2R) [6]
In summary, we found that the DISC1 R264Q variant has higher binding affinity for the dopamine D2 receptor, and results in higher levels of the DISC1-D2R protein complex in conjunction with decreased GSK3α/β Ser21/9 phosphorylation
Summary
Disrupted in schizophrenia 1 (DISC1) is an important susceptibility gene for many psychiatric disorders because it codes for a powerful regulatory protein with a large interacting network that regulates fundamental brain functions [1]. The DISC1 gene was originally discovered in a single large family carrying a chromosomal translocation that severs DISC1 roughly in half [2, 3]. Common DISC1 variants are not the strongest associations with schizophrenia in genome-wide. Our group previously discovered that the DISC1 protein forms a protein-protein complex with the dopamine D2 receptor (D2R), the main target of all existing antipsychotic medications [6]. We found that the DISC1-D2R complex is elevated in post-mortem brain samples from patients with schizophrenia, and in Disc1-L100P mutant mice, an animal model for schizophrenia.
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