Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia.
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.
Gysin
René
R
Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Site de Cery, Prilly, Lausanne, Switzerland.
Kraftsik
Rudolf
R
Boulat
Olivier
O
Bovet
Pierre
P
Conus
Philippe
P
Comte-Krieger
Emily
E
Polari
Andrea
A
Steullet
Pascal
P
Preisig
Martin
M
Teichmann
Tanja
T
Cuénod
Michel
M
Do
Kim Q
KQ
D000328:Adult; D000596:Amino Acids / Q000097:blood; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D056726:Genetic Association Studies; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000235:genetics* / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic; D018967:Risperidone / Q000009:adverse effects / Q000627:therapeutic use; D012559:Schizophrenia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D013438:Sulfhydryl Compounds / Q000097:blood*; D018911:Trinucleotide Repeats
D000596:Amino Acids; D014150:Antipsychotic Agents; D013438:Sulfhydryl Compounds; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D018967:Risperidone