Saturday, 9 March 2013

Methionine synthase and autism

The paper by Christina Muratore and colleagues* (open-access) including Dick Deth and Antonio Persico in the authorship line-up, is the source of today's post. Concerned with quite an important enzyme, methionine synthase (MS), and in particular MS mRNA status in post-mortem frontal cortex samples, the authors report lower levels of MS mRNA in cases of autism. I should add that quite a good overview of this paper can also be found here.
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OK, let's start from the beginning here. Methionine synthase (MS) is an important enzyme concerned with the regeneration of methionine from homocysteine.

Homocysteine or the 'big H' has been mentioned on more than one occasion on this blog with autism in mind (see here and quite recently here). Indeed, the relationship between methionine and homocysteine intersects a number of other important cycles including those related to folate metabolism and the important methyl-giving properties of SAMe (see this post to see what I'm talking about) and further down the line, that all-important glutathione link (see this post). Oh and it's vitamin B12 dependent.

  • In this study, levels of messenger RNA (mRNA) - an important part of the translation of DNA to proteins - for MS were studied in post-mortem brain samples from deceased person who were diagnosed with autism (n=10) and control, not-autism persons (n=41). Ages at death ranged from 4-30 years for the autism group and 28 weeks - 83 years for the control group.
  • Based on the application of qRT-PCR, MS mRNA status across the lifespan of samples included suggested a "striking age-dependent decrease in mRNA levels". In other words, the older the person at time of their death, the less MS mRNA levels were detected in the frontal cortex samples. That being said, they didn't observe corresponding alterations to the level of MS protein despite this age-related change. 
  • With the autism group specifically in mind and depending on the primers used to detect specific domains of MS, mRNA levels were reduced compared to controls. The caveat being that again, levels of MS protein were not different when comparing autism vs. controls. That and the suggestion of a lack of an age-dependent decrease in MS mRNA in autism compared to that observed across control samples. 
  • Oh and the fact that addition of the pro-inflammatory cytokine TNF-α also seemed to affect levels of MS mRNA.
  • There were also some additional findings reported which warrant further attention. So when looking at some of the main players related to that methionine cycle (including methionine, homocysteine, glutathione, etc) in frontal cortex samples (via HPLC) in autism (n=10) and control (n=8) samples, only two parameters came up different: lower, yes lower, homocysteine levels in the autism group alongside lower cystathione levels. Immediately I'm taken back to the recent paper by Jill James discussed quite recently (see here) and their cautions on the use of peripheral markers to denote what might be happening in the brain, albeit with the caveat that the Muratone group was quite a small group.

There are some other details included in this paper regarding "alternative splicing of MS mRNA" but I wouldn't pretend to know all the ins-and-outs of these findings. Suffice to say that there is a suggestion that oxidative stress might have some role to play in what happens to MS both over the course of normal ageing and potentially also in cases of autism.

There's not a great deal more to add about this paper. Yes, again research with a reliance on post-mortem brain samples and all the caveats that go alongside their use (cause of death, comorbidity, etc.). Again however we are presented with some tantalising data about the processes around an important enzyme which has quite a bit of research around it with autism in mind. That alongside some interesting differences found between measures in brain compared with other peripheral tissues which starts to ask some interesting questions about the application of such secondary measures.


* Muratore CR. et al. Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism. PLoS ONE. 2013; 8: e56927.

---------- Muratore, C., Hodgson, N., Trivedi, M., Abdolmaleky, H., Persico, A., Lintas, C., De La Monte, S., & Deth, R. (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) DOI: 10.1371/journal.pone.0056927