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Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism

Muratore CR, Hodgson NW, Trivedi MS, Abdolmaleky HM, Persico AM, Lintas C, De la Monte S, Deth RC. (2013) PLoS One. 8(2) e56927. Epub 2013 Feb 20 

Web URL: View this and related abstracts via PubMed here. Free full text of this article is available online.

Abstract:

The folate and vitamin B12-dependent enzyme methionine synthase (MS) is highly sensitive to cellular oxidative status, and lower MS activity increases production of the antioxidant glutathione, while simultaneously decreasing more than 200 methylation reactions, broadly affecting metabolic activity.

MS mRNA levels in postmortem human cortex from subjects across the lifespan were measured and a dramatic progressive biphasic decrease of more than 400-fold from 28 weeks of gestation to 84 years was observed.

Further analysis revealed alternative splicing of MS mRNA, including deletion of folate-binding domain exons and age-dependent deletion of exons from the cap domain, which protects vitamin B12 (cobalamin) from oxidation. Although three species of MS were evident at the protein level, corresponding to full-length and alternatively spliced mRNA transcripts, decreasing mRNA levels across the lifespan were not associated with significant changes in MS protein or methionine levels.

MS mRNA levels were significantly lower in autistic subjects, especially at younger ages, and this decrease was replicated in cultured human neuronal cells by treatment with TNF-α, whose CSF levels are elevated in autism.

These novel findings suggest that rather than serving as a housekeeping enzyme, MS has a broad and dynamic role in coordinating metabolism in the brain during development and aging. Factors adversely affecting MS activity, such as oxidative stress, can be a source of risk for neurological disorders across the lifespan via their impact on methylation reactions, including epigenetic regulation of gene expression.

FAB RESEARCH COMMENT:

Increased 'oxidative stress' has long been associated with autism and other neurodevelopmental and neurodegenerative disorders.  

These findings highlight a previously unknown role for the enzyme methionine synthase in regulating many aspects of brain metabolism - including oxidative stress - over the lifetime. 

This enzyme helps to regulate glutathione (a key antioxidant), and also requires adequate levels of both folate and B12 as co-factors - both of which have been implicated in autism and other brain disorders, and are already known to be important for normal brain development and function.