International Meeting for Autism Research: Brain Levels of Methionine Synthase MRNA Are Decreased in Autism

Brain Levels of Methionine Synthase MRNA Are Decreased in Autism

Friday, May 21, 2010
Franklin Hall B Level 4 (Philadelphia Marriott Downtown)
1:00 PM
R. Deth , Pharmaceutical Sciences, Northeastern University, Boston, MA
C. Muratore , Pharmaceutical Sciences, Northeastern University, Boston, MA
Background: Methionine synthase (MS) uses folate-derived methyl groups to convert homocysteine to methionine, and its activity is highly sensitive to oxidative stress, which accompanies inflammation. Lower MS activity diverts homocysteine to the synthesis of cysteine and glutathione, and also inhibits methylation reactions, including DNA methylation. Thus MS activity serves as the link between redox status and epigenetic regulation of development. A number of studies have documented oxidative stress in autism, including the presence of brain neuroinflammation.

Objectives: 1. To evaluate age-dependent trends in MS mRNA status in postmortem samples of human cortex. 2. To evaluate MS mRNA status in cortex of autistic subjects vs. age-matched controls.

Methods: Standard PCR and qRT-PCR were carried out using primers targeted to cobalamin-binding and cap domains of MS. Amplified MS transcript levels were normalized to GAPDH levels.  

Results: In control subjects the MS mRNA level displayed a dramatic age-dependent decrease across the lifespan, amounting to a more than 1000-fold reduction from 28 weeks of fetal gestation to 84 yrs of age. From fetal to 18 yrs the decrease in mRNA was rapid, while a slower decrease prevailed thereafter. In autistic subjects (4-30 yrs of age), MS mRNA levels were significantly reduced, and the decrease was greatest for the youngest individuals. The normally present initial phase of decrease was absent, due to the premature occurence of low levels. This pattern is consistent with an adpative response to oxidative stress which can accompany neuroinflammation.

Conclusions: Our studies demonstrate that the level of MS mRNA in the brain is high during fetal development and gradually decreases with age. This decrease is likely to be important for the normal progression of development, via its influence over DNA and histone methylation. MS mRNA levels in the cortex are abnormally low in autism, which is likely to reflect the presence of oxidative stress. Therapies which counteract oxidative stress and promote methylation may be a useful strategy in treating autism.

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