The Redox/Methylation Hypothesis of Autism
Adequate levels of GSH are essential for normal function of all cells, and aerobic metabolism (i.e. mitochondrial utilization of oxygen) places a high demand on GSH status, especially in the brain, which consumes a disproportionately higher amount of oxygen than other tissues. Numerous metabolic mechanisms have evolved to monitor redox status and respond as needed to maintain GSH levels. Key among these is the
folate- and vitamin B12-dependent enzyme methionine synthase, which is inhibited during oxidative stress, resulting in diversion of its homocysteine substrate toward synthesis of GSH rather than converting it to methionine, as illustrated in Figure 1. Under normal circumstances, increased synthesis of GSH restores redox balance, allowing methionine synthase to resume conversion of homocysteine to methionine. However, if oxidative stress is not resolved, methionine synthase activity remains inhibited.24,25
D4SAH
The influence of redox status on methionine synthase is the gateway to regulation of more than 150 different methylation reactions in which a carbon atom is transferred from the donor S-adenosylmethionine (SAM). Perhaps most important for autism is the methylation of sites in DNA and histones that results in inhibition of gene expression as a fundamental step in epigenetic regulation.26
Development can be described as a program of
orchestrated epigenetic transitions resulting in progression of pluripotent stem cells into differentiated cell types with distinctive functional capabilities. Altered patterns of DNA and/or histone methylation can interfere with normal development, resulting in developmental disorders, as has been well-documented in Rett, fragile X, Angelman, and Prader-Willi syndromes.27–30
Accordingly, it is reasonable to propose that impaired methylation occurring in response to xenobiotic-induced oxidative stress would also result in adverse developmental consequences. This is the essence of the redox/methylation hypothesis of autism.
Inhibition of methionine synthase during oxidative stress results in lower levels of methionine and SAM, which is observed in plasma of autistic children. In addition, a portion of the accumulated homocysteine is converted to S-adenosylhomocysteine (SAH), a potent inhibitor of methylation reactions (see Figure 1). Together, the combination of low SAM and high SAH exerts a powerful negative effect on methylation reactions, including methylation of DNA and histone. Other important methylation reactions that are also inhibited during oxidative stress include the synthesis of melatonin and creatine and methylation of catecholamine neurotransmitters. Recent studies have linked changes in DNA methylation with learning and memory creation.31–33
This fascinating
concept implies that perceptual and emotional experiences are able to stably modulate gene expression, resulting in altered neuronal architecture and synaptic connectivity, and can facilitate formation of associative networks. Within this framework, impaired methylation during early years could disrupt processes that are essential for normal cognitive development.
Dopamine-stimulated Phospholipid Methylation
Of particular importance to neuropsychiatry is the ability of dopamine to stimulate methylation of membrane phospholipids, an exclusive activity of the D4 dopamine receptor subtype (see Figure 1), first reported by our laboratory in 1999.34
Phospholipid methylation
D4SAM
Figure 1: Redox and Methylation Pathways in Human Neuronal Cells
Cystine Cysteine Cysteinylglycine GSH
Glial cells (astrocytes)
GSH GSSG
Cysteine Cystathionine Adenosine D4HCY
MethyITHF THF
PP+Pi ATP Dopamine
Methionine synthase
D4MET MET
THF ATP
PP+Pi
Neuron
Sulfur metabolism supports synthesis of the antioxidant glutathione (GSH) and the methionine cycle of methylation (lower right). Methionine synthase regulates the flow of homocysteine (HCY) to either transsulfuration, via cystathionine and cysteine, or to methionine (MET), for synthesis of the methyl donor S-adenosylmethionine (SAM). S-adenosylhomocysteine (SAH) is a powerful inhibitor of methylation reactions. Lower activity of methionine synthase during oxidative stress increases GSH synthesis at the expense of methylation. Methionine synthase also supports the cycle of dopamine-stimulated phospholipid methylation (lower left), carried out by a methionine residue found only in the D4 dopamine receptor, which is impaired during oxidative stress.
HCY MethyITHF SAM Adenosine SAH (-) >150
Methylation reactions
phosphatidylcholine (PC). The newly synthesized PC then ‘flips’ to the outer membrane surface, where it is the predominant phospholipid. Dopamine-stimulated phospholipid methylation therefore affects the asymmetrical distribution of PE versus PC, which can have a very important impact on the function of other neurotransmitter receptors, ion channels, and other membrane proteins located near the D4 receptor. Studies have linked deficits in PC formation with a loss of cognitive abilities, while PC supplementation improves cognition.35,36
The dramatic rise in ADHD prevalence during the past several decades and its 4:1 predominance in males versus females are similar to the pattern seen in autism, suggesting a shared etiology. The D4 receptor gene displays remarkable genetic variability among humans. In a worldwide sample, the overall frequency of the seven-repeat form was about 25%, although in native South Americans it is 80%, while it is less than 3% in native Asians.38
D4 dopamine receptor activity plays an important role in attention, and a specific variant of the D4 receptor gene is widely recognized as an important risk factor for attention-deficit–hyperactivity disorder (ADHD).37
Most, but not all, studies have found
a three- to five-fold higher risk of ADHD associated with the presence of at least one seven-repeat allele.39
The seven-repeat allele shows
evidence of positive selection since its initial appearance 40,000–50,000 years ago, suggesting a beneficial function for an extended period of time, although now it is associated with risk for impaired attention.40
Phosphatidylethanolamine (PE), the particular
phospholipid methylated by the D4 receptor, is localized at the inner surface of the plasma membrane, where it is converted to
US PSYCHIATRY
D4 receptor involvement in attention involves modulation of the frequency at which neural networks fire in synchrony. During
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