Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Site de Cery, Prilly, Lausanne, Switzerland.
Antioxid Redox Signal. 2011 Oct 1;15(7):2003-10. doi: 10.1089/ars.2010.3463. Epub 2010 Oct 30.
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.
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起源的 GSH 失调对血浆硫醇（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。与具有低风险 GCLC GAG TNR 基因型的患者相比，具有合成 GSH 受损的高风险基因型的患者表现出成纤维细胞 GSH 和血浆总半胱氨酸水平降低，以及氧化形式半胱氨酸（胱氨酸）含量增加。还观察到高风险基因型的血浆游离丝氨酸、谷氨酰胺、瓜氨酸和精氨酸水平升高。总之，高风险基因型与一组以血浆硫醇和游离氨基酸水平改变为特征的精神分裂症亚组相关，这反映了氧化还原控制的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用于早期诊断和监测针对精神分裂症氧化还原失调的新型药物有效性的生物标志物谱。
