Impaired glutathione synthesis in schizophrenia:: Convergent genetic and functional evidence
Impaired glutathione synthesis in schizophrenia:: Convergent genetic and functional evidence
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DOI：
10.1073/pnas.0706778104
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发表时间：
2007-10-16
影响因子：
11.1
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.
精神分裂症是一种复杂的多因素大脑疾病，具有遗传成分。汇聚的证据表明，氧化应激和谷胱甘肽（GSH）的缺陷，这种疾病的发病机制。本研究的目的是测试精神分裂症是否与谷胱甘肽合成缺陷有关。培养的皮肤成纤维细胞从精神分裂症患者和对照组的挑战与氧化应激，和参数的限速酶谷胱甘肽合成，谷氨酸半胱氨酸连接酶（GCL），进行了测量。与对照组相比，患者应激细胞的GCL活性降低了26%（P = 0.002）。这种减少与催化GCL亚基（GCLC）蛋白表达减少29%（P < 0.001）相关。在两项独立的病例对照研究中，对GCLC基因中的三核体重复序列（TNR）多态性的遗传分析显示与精神分裂症显著相关。对照组中最常见的TNR基因型7/7更常见[比值比（OR）= 0.6，P = 0.003]，而患者中最罕见的TNR基因型8/8的频率是对照组的3倍（OR = 3.0，P = 0.007）。此外，与疾病相关的基因型的受试者有较低的GCLC蛋白表达（P = 0.017），GCL活性（P = 0.037），和GSH含量（P = 0.004）比受试者的基因型更频繁的控制。总之，这项研究提供了遗传和功能证据，证明在氧化应激条件下合成GSH的能力受损是精神分裂症的一个脆弱因素。
Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit of GSH synthesis. Cultured skin fibroblasts from schizophrenia patients and control subjects were challenged with oxidative stress, and parameters of the ratelimiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P = 0.002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P < 0.001) decreased protein expression of the catalytic GCL subunit (GCLC). Genetic analysis of a trinucleoticle repeat (TNR) polymorphism in the GCLC gene showed a significant association with schizophrenia in two independent case-control studies. The most common TNR genotype 7/7 was more frequent in controls [odds ratio (OR) = 0.6, P = 0.003], whereas the rarest TNR genotype 8/8 was three times more frequent in patients (OR = 3.0, P = 0.007). Moreover, subjects with disease-associated genotypes had lower GCLC protein expression (P = 0.017), GCL activity (P = 0.037), and GSH contents (P = 0.004) than subjects with genotypes that were more frequent in controls. Taken together, the study provides genetic and functional evidence that an impaired capacity to synthesize GSH under conditions of oxidative stress is a vulnerability factor for schizophrenia.