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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, methionine synthase activity is also critical for dopamine-stimulated methylation of membrane phospholipids, a unique activity of the D4 dopamine receptor discovered by our lab in 1999 (Sharma et al., 1999). Thus, oxidative stress caused by impaired GSH synthesis will adversely affect this dopaminergic mechanism.

The physiological role of D4 receptor-mediated phospholipid methylation remains to be fully elucidated, but studies indicate a central role in attention and synchronization of neural networks, both of which are impaired in schizophrenia. The seven-repeat variant of the D4 receptor is considered to be the most important genetic risk factor for ADHD (Swanson et al., 2007), and is also associated with lower IQ, alone or in combination with dopamine transporter variants (Mill et al., 2006). MEG studies in subjects without ADHD showed stronger γ synchronized oscillatory activity during attention in subjects possessing the seven-repeat allele (Demiralp et al., 2007). We recently described a molecular mechanism by which dopamine-stimulated phospholipid methylation could tune neural networks to γ frequency during attention (Kuznetsova et al., 2007), and a restriction in GSH synthesis, as described by Gysin and colleagues, could contribute to impairments of synchronization and attention in schizophrenia.

Oxidative stress-induced inhibition of methionine synthesis also causes accumulation of S-adenosylhomocysteine, a general inhibitor of methylation reactions, affecting more than 150 cellular methylation reactions. Lower COMT activity would augment dopamine levels, while lower activity of DNA and histone methyltransferases would alter epigenetic regulation of gene expression. Thus, a putative role for oxidative stress can be integrated with other proposed theories. Indeed, methylation defects in schizophrenia have been recognized for more than 40 years (Spiro et al., 1965), a hypothesis advanced by Seymour Kety (Kety, 1972), including the replicable finding that methionine administration provokes acute psychosis in schizophrenia subjects but is without effect in normal individuals (Cohen et al., 1974). Despite these early clues, defective sulfur metabolism has received only limited attention. Perhaps the illuminating findings of Gysin and colleagues will reinvigorate interest and encourage schizophrenia researchers to invest the time needed to understand and appreciate this important area of biochemistry.

References:

Regland B, Johansson BV, Grenfeldt B, Hjelmgren LT, Medhus M. Homocysteinemia is a common feature of schizophrenia. J Neural Transm Gen Sect. 1995;100(2):165-9. Abstract

Haidemenos A, Kontis D, Gazi A, Kallai E, Allin M, Lucia B. Plasma homocysteine, folate and B12 in chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Aug 15;31(6):1289-96. Abstract

Sharma A, Kramer ML, Wick PF, Liu D, Chari S, Shim S, Tan W, Ouellette D, Nagata M, DuRand CJ, Kotb M, Deth RC. D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia. Mol Psychiatry. 1999 May;4(3):235-46. Abstract

Swanson JM, Kinsbourne M, Nigg J, Lanphear B, Stefanatos GA, Volkow N, Taylor E, Casey BJ, Castellanos FX, Wadhwa PD. Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol Rev. 2007 Mar;17(1):39-59. Abstract

Mill J, Caspi A, Williams BS, Craig I, Taylor A, Polo-Tomas M, Berridge CW, Poulton R, Moffitt TE. Prediction of heterogeneity in intelligence and adult prognosis by genetic polymorphisms in the dopamine system among children with attention-deficit/hyperactivity disorder: evidence from 2 birth cohorts. Arch Gen Psychiatry. 2006 Apr;63(4):462-9. Abstract

Demiralp T, Herrmann CS, Erdal ME, Ergenoglu T, Keskin YH, Ergen M, Beydagi H. DRD4 and DAT1 polymorphisms modulate human gamma band responses. Cereb Cortex. 2007 May;17(5):1007-19. Abstract

Kuznetsova AY, Deth RC. A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated phospholipid methylation. J Comput Neurosci. 2007 Oct 11; [Epub ahead of print] Abstract

Spiro HR, Schimke RN, Welch JP. Schizophrenia in a patient with a defect in methionine metabolism. J Nerv Ment Dis. 1965 Sep;141(3):285-90. Abstract

Kety SS. Toward hypotheses for a biochemical component in the vulnerability to schizophrenia. Semin Psychiatry. 1972 Aug;4(3):233-8. Abstract

Cohen SM, Nichols A, Wyatt R, Pollin W. The administration of methionine to chronic schizophrenic patients: a review of ten studies. Biol Psychiatry. 1974 Apr;8(2):209-25. Abstract

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