Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence.
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.
Gysin
René
R
Center for Psychiatric Neuroscience, Department of Psychiatry, University Hospital Center and University of Lausanne, 1008 Prilly-Lausanne, Switzerland. rene.gysin@chuv.ch
Kraftsik
Rudolf
R
Sandell
Julie
J
Bovet
Pierre
P
Chappuis
Céline
C
Conus
Philippe
P
Deppen
Patricia
P
Preisig
Martin
M
Ruiz
Viviane
V
Steullet
Pascal
P
Tosic
Mirjana
M
Werge
Thomas
T
Cuénod
Michel
M
Do
Kim Q
KQ
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
D021122:Protein Subunits; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione