Genetic Dysregulation of Glutathione Synthesis Predicts Alteration of Plasma Thiol Redox Status in Schizophrenia
Genetic Dysregulation of Glutathione Synthesis Predicts Alteration of Plasma Thiol Redox Status in Schizophrenia
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DOI：
10.1089/ars.2010.3463
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发表时间：
2011-10-01
影响因子：
6.6
通讯作者：
Do, Kim Q.
中科院分区：
文献类型：
--
作者：
Gysin, Rene;Kraftsik, Rudolf;Do, Kim Q.
遗传研究表明，精神分裂症与谷氨酸半胱氨酸连接酶（GCL）催化亚基（GCLC）中的GAG三核苷酸重复（TNR）多态性之间存在关联，GCL是谷胱甘肽（GSH）合成的关键酶。本研究旨在分析遗传来源的GSH失调对血浆巯基（总半胱氨酸、同型半胱氨酸和半胱氨酸-甘氨酸）和其他游离氨基酸水平以及成纤维细胞培养物GSH水平的影响。还比较了患者和对照组之间的血浆硫醇水平。与低风险GCLC GAG TNR基因型患者相比，具有GSH合成受损的高风险基因型患者显示成纤维细胞GSH和血浆总半胱氨酸水平降低，氧化形式的半胱氨酸（胱氨酸）含量增加。在高风险基因型中也观察到血浆游离丝氨酸、谷氨酰胺、瓜氨酸和精氨酸水平升高。两者合计，高风险基因型与精神分裂症的一个亚组，其特征是改变血浆巯基和游离氨基酸水平，反映了氧化还原控制失调和对氧化应激的易感性增加。这种改变的模式可能有助于开发一种生物标志物，用于早期诊断和监测精神分裂症中靶向氧化还原失调的新药的有效性。抗氧化剂。氧化还原信号。15，2003-2010年。
Genetic studies have shown an association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the catalytic subunit (GCLC) of the glutamate cysteine ligase (GCL), the key enzyme for glutathione (GSH) synthesis. The present study was aimed at analyzing the influence of a GSH dysregulation of genetic origin on plasma thiols (total cysteine, homocysteine, and cysteine-glycine) and other free amino acid levels as well as fibroblast cultures GSH levels. Plasma thiols levels were also compared between patients and controls. As compared with patients with a low-risk GCLC GAG TNR genotype, patients with a high-risk genotype, having an impaired GSH synthesis, displayed a decrease of fibroblast GSH and plasma total cysteine levels, and an increase of the oxidized form of cysteine (cystine) content. Increased levels of plasma free serine, glutamine, citrulline, and arginine were also observed in the high-risk genotype. Taken together, the high-risk genotypes were associated with a subgroup of schizophrenia characterized by altered plasma thiols and free amino acid levels that reflect a dysregulation of redox control and an increased susceptibility to oxidative stress. This altered pattern potentially contributes to the development of a biomarker profile useful for early diagnosis and monitoring the effectiveness of novel drugs targeting redox dysregulation in schizophrenia. Antioxid. Redox Signal. 15, 2003-2010.