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.

中文翻译：

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DISC1 R264Q变体增加了对多巴胺D2受体的亲和力，并增加了GSK3活性。

精神分裂症患者1（DISC1）基因编码的脚手架蛋白参与许多神经功能，如神经发生，神经分化，胚胎神经元迁移和神经递质信号传导。DISC1最初与一个家族的精神分裂症有关，具有明显的突变，即染色体易位，切断了基因的中点（aa 598）。在普通人群中，一些常见的DISC1变体也与精神分裂症有关，但是距离染色体易位断点较远的那些可能具有不同的功能影响。我们先前曾报道DISC1与多巴胺D2受体（D2R）形成蛋白质复合物，多巴胺D2R是抗精神病药物的主要靶标。D2R-DISC1复合物在精神分裂症患者的脑组织中升高，并促进糖原合酶激酶（GSK）-3信号传导。DISC1 R264Q变体位于与D2R结合的区域内，我们发现这种多态性增加了DISC1对D2R的亲和力，并促进了GSK3活性。我们的研究结果提示这种常见的多态性可能会影响与精神病和精神分裂症有关的脑功能方面的可能机制。这为精神分裂症的分子机制提供了更多的见解，可以在新药理学治疗的开发中加以利用。我们的研究结果提示这种常见的多态性可能会影响与精神病和精神分裂症有关的脑功能方面的可能机制。这为精神分裂症的分子机制提供了更多的见解，可以在新药理学治疗的开发中加以利用。我们的研究结果提示这种常见的多态性可能会影响与精神病和精神分裂症有关的脑功能方面的可能机制。这为精神分裂症的分子机制提供了更多的见解，可以在新药理学治疗的开发中加以利用。