title: Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence.
abstract: 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 rate-limiting 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 trinucleotide 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.
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, University Hospital Center and University of Lausanne, 1008 Prilly-Lausanne, Switzerland. rene.gysin@chuv.ch
authors.forename: René
authors.initials: R
authors.lastname: Gysin
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kraftsik
authors.forename: Julie
authors.initials: J
authors.lastname: Sandell
authors.forename: Pierre
authors.initials: P
authors.lastname: Bovet
authors.forename: Céline
authors.initials: C
authors.lastname: Chappuis
authors.forename: Philippe
authors.initials: P
authors.lastname: Conus
authors.forename: Patricia
authors.initials: P
authors.lastname: Deppen
authors.forename: Martin
authors.initials: M
authors.lastname: Preisig
authors.forename: Viviane
authors.initials: V
authors.lastname: Ruiz
authors.forename: Pascal
authors.initials: P
authors.lastname: Steullet
authors.forename: Mirjana
authors.initials: M
authors.lastname: Tosic
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Michel
authors.initials: M
authors.lastname: Cuénod
authors.forename: Kim Q
authors.initials: KQ
authors.lastname: Do
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005721:Glutamate-Cysteine Ligase / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D005978:Glutathione / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D021122:Protein Subunits / Q000032:analysis / Q000172:deficiency / Q000235:genetics; D012559:Schizophrenia / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000201:enzymology; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D021122:Protein Subunits; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione