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Schizophrenia: a Case of Faulty Redox Detox?

24 October 2007. A research collaboration between Swiss and Danish researchers provides new genetic and biochemical evidence that neural damage from oxidative stress may play a role in the pathogenesis of schizophrenia. In particular, the new study, published in the October 16 issue of PNAS, implicates a trinucleotide repeat (TNR) polymorphism in a gene that is crucial for the synthesis of the antioxidant peptide glutathione, which plays a protective role in the brain by scavenging for reactive oxygen species and neutralizing them.

Reactive oxygen species are important for cell signaling (so-called redox signaling) and the immune response, but they are cytotoxic, and adequate synthesis of glutathione is essential for maintaining a balanced intracellular reducing environment that keeps destructive peroxides and free radicals in check. Gene mutations that impair glutathione synthesis have been associated with a number of serious diseases and pathologies, including Parkinson’s disease, Alzheimer’s disease, atherosclerosis, myocardial infarction, and mental retardation. Based on several previous findings of low glutathione levels in cerebrospinal fluid and postmortem tissue from patients with schizophrenia (e.g., Do et al., 2000), Kim Q. Do and colleagues at the University of Lausanne have proposed a “redox dysregulation” hypothesis of the disorder.

Anatomy of a scavenger
Glutathione is synthesized in two consecutive enzymatic reactions, the first catalyzed by glutamate cysteine ligase (GCL) and the second by glutathione synthetase (GSS). GCL, the rate-limiting enzyme in glutathione synthesis, has catalytic and modulatory subunits. A 2006 study from the Lausanne group had found that expression of both GSS and the modulatory subunit of GCL was reduced in cultured skin fibroblasts derived from schizophrenia patients, and reported an association between schizophrenia and certain alleles of the gene for GCL’s modulatory subunit.

In the new work, first author René Gysin and colleagues joined forces with Thomas Werge at Copenhagen University Hospital to more directly address the question of whether glutathione synthesis is compromised in schizophrenia.

To do so, the researchers again cultured fibroblasts obtained by skin biopsy from Swiss and Danish patients with schizophrenia and healthy controls, as assessed by Diagnostic Interview for Genetic Studies (DIGS) and DSM-IV criteria. The fibroblasts were treated with tert-butylhydroquinone (TBHQ), a phenolic compound known to induce the expression of phase 2 antioxidant genes—including those for GCL’s two subunits—and thereby increasing glutathione synthesis.

In the Swiss sample, GCL activity after TBHQ treatment was 26 percent lower in patients with schizophrenia than in controls. Protein expression of the GCL catalytic subunit (but not the modulatory subunit) was also lower in patients, by 22 percent.

A repeated problem
The GCL catalytic subunit gene, on chromosome 6p12, contains a TNR polymorphism with seven, eight, or nine guanine-adenine-guanine (GAG) repeats (Walsh et al., 2001). In both the Swiss and Danish samples, there was a marked difference in the distribution of these alleles between patients and controls. In general, the 8 and 9 alleles were far more common among the patients, whereas the 7 allele was found more often in controls. In the Danish sample, the 8/8 genotype was three times more common in patients versus controls, but the 7/7 genotype, common in controls, appeared to exert a protective effect.

Based on these findings, the researchers hypothesized that the higher number of GAG repeats in patients compromised glutathione synthesis. To explore this question, they divided the Swiss sample into “low-risk” (7/7 and 7/9 genotypes) and “high-risk” (7/8, 8/8, 8/9, and 9/9 genotypes) groups. After TBHQ treatment of fibroblasts from each group, the authors found significantly lower GCL activity, catalytic subunit expression and overall glutathione content in the high-risk group.

GAGs with serious consequences
Gysin and colleagues propose that reduced glutathione synthesis caused by the GAG TNR polymorphism in the gene for GCL’s catalytic subunit may conspire with risk factors associated with both oxidative stress and schizophrenia, causing aberrant synapse development and the perceptual, cognitive, and behavioral symptoms that characterize the schizophrenia phenotype. For example, obstetrical complications, inflammation, and viral infections, all associated with schizophrenia, are also known to cause oxidative stress. In addition, psychological stress can cause oxidative stress via the hypothalamic-pituitary-adrenal axis in the dopamine-rich brain areas affected in schizophrenia.

Summing up, the authors write that the new findings “provide evidence for a genetic source of the redox dysregulation in schizophrenia,” and add that the GAG TNR polymorphism “may serve as a marker to identify individuals at risk [and to] gather a complete picture of genetic risk factors of schizophrenia in the [glutathione] and oxidative stress associated pathways.”—Peter Farley.

References:
Gysin R, Kraftsik R, Sandell J, Bovet P, Chappuis C, Conus P, Deppen P, Preisig M, Ruiz V, Steullet P, Tosic M, Werge T, Cuénod M, Do KQ. Impaired glutathione synthesis in schizophrenia: Convergent genetic and functional evidence. Proc Natl Acad Sci USA. 2007 Oct 16;104(42):16621-6. Abstract

Do KQ, Trabesinger AH, Kirsten-Krüger M, Lauer CJ, Dydak U, Hell D, Holsboer F, Boesiger P, Cuénod M. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000 Oct;12(10):3721-8. Abstract

 
Comments on News and Primary Papers
Comment by:  Richard Deth
Submitted 25 November 2007 Posted 28 November 2007
  I recommend the Primary Papers

Identification of a limitation in the capacity for glutathione (GSH) synthesis by Gysin and colleagues raises several questions: "How could a redox problem (i.e., oxidative stress) lead to schizophrenia?” and "Does this finding mesh with other hypotheses?"

All cells must maintain sufficient levels of GSH to survive collateral damage from oxidative metabolism, and a number of adaptive mechanisms have evolved to meet this need. One important example is inhibition of the enzyme methionine synthase by oxidative stress. The higher the oxidative stress level, the greater the inhibition of its methylation of homocysteine to methionine, allowing the accumulating homocysteine to be diverted to GSH synthesis via the trans-sulfuration pathway. Homocysteine levels are elevated in schizophrenia, especially, but not exclusively, in first-episode males (Regland et al., 1995; Haidemenos et al., 2007), implying that methionine synthase is inhibited, perhaps by oxidative stress. Importantly,...  Read more


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