The metabolism of sulfur (S) compounds concurs to the maintain of cell homeostasis and tissue integrity in the human body. Sulfur chemical species act in all cells as anti-oxidant/scavenging agents or regulators of membrane stability/excitability. At the same time, they also exert tissue-dependent functions behaving as protective molecules of the liver and cardiovascular system, as modulators of the immune response, gut activity and CNS neurotransmitter signaling.
The involvement of S compounds in human complex, chronic, disabling diseases at multifaceted pathogenesis is actually under investigation: altered levels of S metabolites could be in fact bio-indicators of impaired oxidation state in the body and their unbalance could be risk factors for disease onset. The perspectives of these kinds of analyses would be the adoption of more valuable, personalized therapeutics protocols for Schizophrenia.
Schizophrenia, a devastating behavioral disease, is characterized by delusions, thought disorder, hallucinations, psychosis and cognitive deficits. Schizophrenia affects the most basic human processes of perception, emotion and judgment at different degrees of severity. As for autism, genetics studies of schizophrenia have shown heterogeneous and complex profiles, suggesting that the disease could originate from common and rare variants, but also from epigenetics alterations. Beside the dopaminergic/serotonin hypothesis, other biochemical substrates are supposed to underlie schizophrenia and psychosis.
As regards the topic of this review, an old story relates S-AAs, Met biochemistry and schizophrenia: in the early ‘60s, some authors observed that administration of Met together monoaminooxydase inhibitors (MAOI) worsened symptoms in schizophrenic patients. Since that time, after a long period of disregard, a renovated interest is now emerging on Met pathways in neuropsychiatric disorders, depression, delusion and negative symptoms of psychoticrelated disorders and schizophrenia.
First, genetic studies have involved genes of S biochemistry as vulnerability factors of the disease and a genetic hypothesis underlying psychosis and altered HCys metabolism has been also formulated. Differently from autism, schizophrenic and bipolar psychotic patients characterized by Met metabolism dysfunction, consistently show elevated HCys plasma levels. Moreover, as a risk factor to develop the disease, changes and variants of the 1 C cycle enzymes have been reported: in particular, as for ASD, the HCys remethylation enzyme MTHFR 677C>T has been linked to psychotic behavior. Other S-related genes have been implicated in schizophrenia, as DNA variation of SULT4a1, a sulfotransferase isoform expressed in the brain only which specifically promotes sulfation of catecholamine, or Met sulfone reductase.
Plasma levels studies have linked variation of plasma S-AAs as Met and Cys to different phases of this invalidating mental illness: for instance, Met was found lower in psychotic patients unresponsive to atypical antipsychotic drugs, whereas high Met was reported in drugfree patients with schizophrenia. Others have shown low S-AAs levels in psychosis. Finally, some authors have reported that an altered plasma Tau/Met-Ser ratio can be a powerful biomarker of acute psychosis. Investigations on platelet STs in patients with mood disorders have shown an increased enzyme activity in bipolar disorder. These data, albeit in part discordant, suggest an imbalance of S metabolism in psychosis and schizophrenia. As aforementioned, a number of studies have reported increased circulating levels of HCys in schizophrenic and bipolar patients.
High HCys in schizophrenia has been related to the above reported genetic variations, but several new findings are also in support of epigenetic causes. The amount of HCys in tissues and blood depends from Met metabolism balance and, in particular, from the relative activities of Met transmethylation and remethylation enzymes, regulated by the intake of folic acid and B group vitamins. High circulating levels of HCys have been related not only to neuropsychiatric disorders but also to cardiovascular diseases, diabetes and neurodegenerative diseases, indicating that its metabolism exert pleiotropic effects in the body. An interesting finding has shown the significant reduction of transthyretin, a protein transporter of the circulating thyroid hormone T4 and retinol, in psychosis. Since HCys reduces the active form of transthyretin, cognitive impairment in psychosis and schizophrenia could be linked to high HCys levels and low transthyretin.
The hypothesis formulated by Costa and coauthors starts instead from the early Met studies on schizophrenia and relates these findings to an hypermethylation of specific genes, provoking their down-regulation, in schizophrenic patients. The susceptibility seems linked to gender variables. Interestingly, Met metabolism and dopamine transmission have been found interlaced in schizophrenia, a finding needing replication. Thus, schizophrenia and psychosis are characterized by heterogeneous genetics and, at a different degree, by dopamine/ monoamine imbalance, altered sulfation, S metabolism changes and, possibly, hypermethylation, gene expression down-regulation patterns and transthyretin deficit. Mytochondrial dysfunctions are also emerging.
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