From the Shanghai Mental Health Centre, Shanghai Jiaotong University, School of Medicine, Shanghai, China (Wang, Xu, Yuan, Li, Zhang, Liu); the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont. (Su, Samsom, Wong, Liu); the National Clinical Research Centre for Mental Disorders, Beijing AnDing Hospital, Capital Medical University, Beijing, China (Yang, Dong, Zhou); the Department of Pharmacology, University of Toronto, Toronto, Ont. (Samsom, Wong); the Institute of Medical Science, University of Toronto, Toronto, Ont. (Wong, Liu); the Department of Psychiatry, University of Toronto, Toronto, Ont. (Wong, Liu); the Department of Physiology, University of Toronto, Toronto, Ont. (Liu).
From the Shanghai Mental Health Centre, Shanghai Jiaotong University, School of Medicine, Shanghai, China (Wang, Xu, Yuan, Li, Zhang, Liu); the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont. (Su, Samsom, Wong, Liu); the National Clinical Research Centre for Mental Disorders, Beijing AnDing Hospital, Capital Medical University, Beijing, China (Yang, Dong, Zhou); the Department of Pharmacology, University of Toronto, Toronto, Ont. (Samsom, Wong); the Institute of Medical Science, University of Toronto, Toronto, Ont. (Wong, Liu); the Department of Psychiatry, University of Toronto, Toronto, Ont. (Wong, Liu); the Department of Physiology, University of Toronto, Toronto, Ont. (Liu)
J Psychiatry Neurosci. 2022 Mar 31;47(2):E134-E147. doi: 10.1503/jpn.210145. Print 2022 Mar-Apr.
For decades, the dopamine D2 receptor (D2R) has been known as the main target of antipsychotic medications, but the mechanism for antipsychotic effects beyond this pharmacological target remains unclear. Disrupted-in-schizophrenia 1 () is a gene implicated in the etiology of schizophrenia, and we have found elevated levels of the D2R-DISC1 complex in the postmortem brain tissue of patients with schizophrenia.
We used coimmunoprecipitation to measure D2R-DISC1 complex levels in peripheral blood samples from patients with schizophrenia and unaffected controls in 3 cohorts (including males and females) from different hospitals. We also used label-free mass spectrometry to conduct proteomic analysis of these samples.
Levels of the D2R-DISC1 complex were elevated in the peripheral blood samples of patients with schizophrenia from 3 independent cohorts, and were normalized with antipsychotic treatment. Proteomic analysis of the blood samples from patients with high D2R-DISC1 complex levels that were normalized with antipsychotic treatment revealed a number of altered proteins and pathways associated with D2R, DISC1 and the D2R-DISC1 complex. We identified additional proteins and pathways that were associated with antipsychotic treatment in schizophrenia, and that may also be novel targets for schizophrenia treatment.
Sample sizes were relatively small, but were sufficient to detect associations between D2R-DISC1 levels, schizophrenia and treatment response. The relevance of leukocyte changes to the symptoms of schizophrenia is unknown. The coimmunoprecipitation lanes included several nonspecific bands.
Levels of the D2R-DISC1 complex were elevated in patients with schizophrenia and reduced with antipsychotic treatment. This finding reinforces the independent role of each protein in schizophrenia. Our results enhanced our understanding of the molecular pathways involved in schizophrenia and in antipsychotic medications, and identified novel potential molecular targets for treating schizophrenia.
几十年来，多巴胺 D2 受体 (D2R) 一直是抗精神病药物的主要靶点，但这种药物靶点之外的抗精神病作用机制仍不清楚。分裂症相关蛋白 1 () 是一种与精神分裂症发病机制相关的基因，我们在精神分裂症患者的死后脑组织中发现了 D2R-DISC1 复合物水平升高。
我们使用共免疫沉淀法在来自不同医院的 3 个队列（包括男性和女性）的精神分裂症患者和未受影响的对照者的外周血样本中测量 D2R-DISC1 复合物水平。我们还使用无标记质谱法对这些样本进行蛋白质组学分析。
来自 3 个独立队列的精神分裂症患者外周血样本中的 D2R-DISC1 复合物水平升高，经抗精神病治疗后可恢复正常。用抗精神病药物治疗使 D2R-DISC1 复合物水平恢复正常的患者血液样本的蛋白质组学分析显示，与 D2R、DISC1 和 D2R-DISC1 复合物相关的许多蛋白和途径发生了改变。我们还发现了与精神分裂症中的抗精神病治疗相关的其他蛋白和途径，它们也可能是精神分裂症治疗的新靶点。
样本量相对较小，但足以检测 D2R-DISC1 水平、精神分裂症和治疗反应之间的关联。白细胞变化与精神分裂症症状的相关性尚不清楚。共免疫沉淀的泳道包括几个非特异性条带。
精神分裂症患者的 D2R-DISC1 复合物水平升高，用抗精神病药物治疗后降低。这一发现强化了每种蛋白在精神分裂症中的独立作用。我们的研究结果增强了我们对精神分裂症和抗精神病药物相关分子途径的理解，并确定了治疗精神分裂症的新潜在分子靶点。
