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Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an
Christina R Muratore1, Nathaniel W Hodgson, Malav S Trivedi
1Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA.
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.
Insights
Methionine synthase (MS) enzyme activity decreases significantly with age and in autism. This decline impacts brain metabolism and methylation, potentially increasing neurological disorder risk.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Methionine synthase (MS) is a critical enzyme dependent on folate and vitamin B12.
- MS activity is sensitive to oxidative stress, influencing glutathione production and methylation reactions.
- Methylation is vital for metabolic activity and epigenetic regulation.
Purpose of the Study:
- To investigate age-related changes in methionine synthase (MS) mRNA and protein levels in the human brain.
- To explore the impact of alternative splicing on MS function.
- To examine the association between MS mRNA levels, autism, and oxidative stress markers.
Main Methods:
- Quantification of MS mRNA levels in postmortem human cortical tissue across the lifespan.
- Analysis of MS alternative splicing variants.
- Measurement of MS protein and methionine levels.
- Comparison of MS mRNA levels in autistic versus neurotypical subjects.
- In vitro studies using cultured neuronal cells treated with TNF-α.
Main Results:
- MS mRNA levels showed a dramatic biphasic decrease from gestation to 84 years.
- Alternative splicing of MS mRNA, including exon deletions, was observed and varied with age.
- MS mRNA levels were significantly lower in autistic subjects, particularly at younger ages.
- Decreased MS mRNA levels were replicated in neuronal cells treated with TNF-α.
- No significant changes in MS protein or methionine levels correlated with decreasing mRNA.
Conclusions:
- Methionine synthase plays a dynamic role in brain metabolism and development, not just a housekeeping function.
- Age-related decline and reduced MS mRNA levels in autism suggest a link to oxidative stress.
- Dysregulation of MS may contribute to neurological disorders through altered methylation and epigenetic processes.
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