Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism

Christina R. Muratore, Nathaniel W. Hodgson, Malav S. Trivedi, Hamid M. Abdolmaleky, Antonio M. Persico, Carla Lintas, Suzanne De La Monte, Richard C. Deth

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Article numbere56927
JournalPLoS One
Volume8
Issue number2
DOIs
Publication statusPublished - Feb 20 2013

Fingerprint

5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
methionine synthase
cerebral cortex
alternative splicing
Alternative Splicing
Autistic Disorder
Cerebral Cortex
Messenger RNA
vitamin B12
Vitamin B 12
Methylation
Folic Acid
folic acid
methylation
exons
Exons
autism
Housekeeping
Oxidative stress
nervous system diseases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Muratore, C. R., Hodgson, N. W., Trivedi, M. S., Abdolmaleky, H. M., Persico, A. M., Lintas, C., ... Deth, R. C. (2013). Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism. PLoS One, 8(2), [e56927]. https://doi.org/10.1371/journal.pone.0056927

Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism. / Muratore, Christina R.; Hodgson, Nathaniel W.; Trivedi, Malav S.; Abdolmaleky, Hamid M.; Persico, Antonio M.; Lintas, Carla; De La Monte, Suzanne; Deth, Richard C.

In: PLoS One, Vol. 8, No. 2, e56927, 20.02.2013.

Research output: Contribution to journalArticle

Muratore, CR, Hodgson, NW, Trivedi, MS, Abdolmaleky, HM, Persico, AM, Lintas, C, De La Monte, S & Deth, RC 2013, 'Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism', PLoS One, vol. 8, no. 2, e56927. https://doi.org/10.1371/journal.pone.0056927
Muratore, Christina R. ; Hodgson, Nathaniel W. ; Trivedi, Malav S. ; Abdolmaleky, Hamid M. ; Persico, Antonio M. ; Lintas, Carla ; De La Monte, Suzanne ; Deth, Richard C. / Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism. In: PLoS One. 2013 ; Vol. 8, No. 2.
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