Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism

Figure 1

Pathophysiology of autism based on our findings showing the impact of reactive oxygen species (ROS) at different levels of intermediary metabolism and the consequences of brain 5-methyltetrahydrofolate (5-methyl THF) deficiency due to FRα autoimmunity. ROS inhibits B12-methionine synthase (B12-MS) activity and stimulates cystathionine beta synthase (CBS) activity, shifting the homocysteine accumulation from the methionine cycle into the transsulfuration pathway with increased production of the natural antioxidant glutathione. Superoxide anions also react with NO at the level of NO-synthase (NOS1) to form peroxynitrite instead of NO, which predisposes to apoptosis and nitrosylation of tyrosine and cysteine. Nitrosative stress affects activity of tryptophan (TPH2) and tyrosine hydroxylases (TH), the rate-limiting enzymes for serotonin, and dopamine synthesis. In addition, ROS catabolize 5-methyl-THF and impair folate uptake and transcellular transport across the choroid plexus and placental barriers due to interaction with FRα and RFC1 folate transporters. FRα autoantibodies also impair folate transport to the fetus and brain. The resulting brain folate deficiency predisposes to reduce SAM production and SAM-dependent methyl-transfer reactions and reduces purine and thymidine synthesis with diminished GTP and BH4 production. The diminished BH4 availability as the shared cofactor of the enzymes TH, TPH2, and NOS1 will therefore reduce their enzyme activity. Reduction of the activated methyl group donor SAM downregulates DNA methylation and affects posttranslational modifications of histones (methylation and trimethylation of histones), thereby impeding the homeostatic balance between gene transcription and silencing. In addition, folate deficiency is accompanied by overexpression of histone deacetylases, which further leads to abnormal gene silencing. The shutdown in expression of specific sets of genes will affect neuronal growth, pruning, and differentiation. Abbreviations: GTPCH: GTP-cyclohydrolase I; Arg: arginine; Cyst: cysteine; Tyr: tyrosine; Trp: tryptophan; MTHFR: methylenetetrahydrofolate reductase; RFC1: reduced folate carrier-1 (reproduced with permission from [20]).