Dr. Richard Deth Viewing the Brain from a Redox Perspective: Growth Factors, GF/CF, and Beyond

The brain develops and functions in a unique redox environment, with only limited availability of the sulfur amino acid cysteine to support synthesis of the antioxidant glutathione (GSH). As a consequence, changes in cysteine uptake exert exceptionally powerful control over neuronal function. Our recent studies show that neurotrophic growth factors increase cysteine uptake and increase GSH levels, while opiates (morphine and gluten/casein-derived peptides), decrease uptake and lower GSH levels. The latter observation helps explain the beneficial effect of a GF/CF diet in autism. The folate and B12-dependent enzyme methionine synthase is highly responsive to redox status in neuronal cells, which allows growth factors to regulate gene expression via epigenetic mechanisms. The level of methionine synthase mRNA in human cortex decreases several hundred-fold across the lifespan, and is significantly reduced in autistic subjects compared to age-matched control subjects, especially at a younger age. Proinflammatory cytokines, such as TNF-alpha, inhibit cysteine uptake, inhibit methylation and lower the level of methionine synthase mRNA. Together these findings illustrate the central role that redox plays in guiding brain development as well as supporting its ongoing function. Agents which disrupt normal redox status can cause developmental disorders via their effects on methylation and gene expression.

Richard Deth, PhD is a professor of pharmacology in the Department of Pharmaceutical Sciences at Northeastern University in Boston. His laboratory was first to discover a novel signaling activity of D4 dopamine receptors, involving dopamine-stimulated phospholipid methylation. This signaling mechanism is involved in synchronization of neural networks and is highly sensitive to neurodevelopmental toxins and to agents that cause oxidative stress. Currently his lab is focused on elucidating the intersecting roles of redox regulation and methylation in neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.

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