Fournier M, Monin A, Ferrari C, Baumann P S, Conus P, Do K
Department of Psychiatry, Center for Psychiatric Neuroscience, Lausanne University Hospital, Switzerland, Switzerland.
Department of Psychiatry, Service of general psychiatry, Lausanne University Hospital, Switzerland, Switzerland.
NPJ Schizophr. 2017 Sep 18;3(1):31. doi: 10.1038/s41537-017-0035-3.
xCT is the specific chain of the cystine/glutamate antiporter, which is widely reported to support anti-oxidant defenses in vivo. xCT is therefore at the crossroads between two processes that are involved in schizophrenia: oxidative stress and glutamatergic neurotransmission. But data from human studies implicating xCT in the illness and clarifying the upstream mechanisms of xCT imbalance are still scarce. Low glutathione (GSH) levels and genetic risk in GCLC (Glutamate-Cysteine Ligase Catalytic subunit), the gene of limiting synthesizing enzyme for GSH, are both associated with schizophrenia. In the present study, we aimed at determining if xCT regulation by the redox system is involved in schizophrenia pathophysiology. We assessed whether modulating GCLC expression impact on xCT expression and activity (i) in fibroblasts from patients and controls with different GCLC genotypes which are known to affect GCLC regulation and GSH levels; (ii) in rat brain glial cells, i.e., astrocytes and oligodendrocytes, with a knock-down of GCLC. Our results highlight that decreased GCLC expression leads to an upregulation of xCT levels in patients' fibroblasts as well as in astrocytes. These results support the implication of xCT dysregulation in illness pathophysiology and further indicate that it can result from redox changes. Additionally, we showed that these anomalies may already take place at early stages of psychosis and be more prominent in a subgroup of patients with GCLC high-risk genotypes. These data add to the existing evidence identifying the inflammatory/redox systems as important targets to treat schizophrenia already at early stages.
ANTIOXIDANT DEFICIT INCREASES A KEY NEUROTRANSMITTER TRANSPORTER: Deficit of antioxidant synthesis in schizophrenia leads to oxidative stress and changes in neurotransmitter transporter. Led by Kim Do, a team of researchers from Lausanne University in Switzerland investigated the role of the cell-surface transport protein xCT in schizophrenia. They found that an enzyme responsible for antioxidant production is disturbed in patients. This leads to decreased antioxidant levels and consequently to oxidative stress-i.e. the accumulation of reactive oxygen molecules, damaging the cells component and impairing cell functioning-which in turn affects the functioning of the antioxidant pathway, including xCT. xCT, which exports the neurotransmitter glutamate, is thus overproduced in schizophrenia. The resulting increase of neurotransmitter activity, alongside the increase in oxidative stress, is thought to play a major role in the pathophysiology of schizophrenia, including at early stages of the disease.
xCT是胱氨酸/谷氨酸逆向转运体的特定链,广泛报道其在体内支持抗氧化防御。因此,xCT处于精神分裂症所涉及的两个过程的交叉点:氧化应激和谷氨酸能神经传递。但是,关于xCT与该疾病相关以及阐明xCT失衡上游机制的人体研究数据仍然很少。谷胱甘肽(GSH)水平低以及GSH限制合成酶基因GCLC(谷氨酸 - 半胱氨酸连接酶催化亚基)中的遗传风险均与精神分裂症有关。在本研究中,我们旨在确定氧化还原系统对xCT的调节是否参与精神分裂症的病理生理过程。我们评估了调节GCLC表达对xCT表达和活性的影响:(i)在来自已知影响GCLC调节和GSH水平的不同GCLC基因型的患者和对照的成纤维细胞中;(ii)在大鼠脑胶质细胞,即星形胶质细胞和少突胶质细胞中,通过敲低GCLC来评估。我们的结果表明,GCLC表达降低导致患者成纤维细胞以及星形胶质细胞中xCT水平上调。这些结果支持xCT失调参与疾病病理生理过程,并进一步表明其可能由氧化还原变化引起。此外,我们表明这些异常可能在精神病早期就已发生,并且在具有GCLC高风险基因型的患者亚组中更为突出。这些数据补充了现有证据,表明炎症/氧化还原系统是早期治疗精神分裂症的重要靶点。
抗氧化剂缺乏增加关键神经递质转运体:精神分裂症中抗氧化剂合成的缺乏导致氧化应激和神经递质转运体的变化。由瑞士洛桑大学的金杜(Kim Do)带领的一组研究人员调查了细胞表面转运蛋白xCT在精神分裂症中的作用。他们发现,负责抗氧化剂产生的一种酶在患者体内受到干扰。这导致抗氧化剂水平降低,进而导致氧化应激,即活性氧分子的积累,损害细胞成分并损害细胞功能,这反过来又影响抗氧化途径的功能,包括xCT。输出神经递质谷氨酸的xCT在精神分裂症中因此过度产生。由此导致的神经递质活性增加,以及氧化应激的增加,被认为在精神分裂症的病理生理过程中起主要作用,包括在疾病的早期阶段。