Pristine cysteine-matically done

First of all, sorry for the terrible pun that makes up the post title. What can I say apart from (a) what else rhymes with the amino acid cysteine? and (b) I'd probably make a terrible tabloid newspaper headline maker unlikely to come up with something like this British classic.

In this post I want to focus on a paper by Mostafa Waly and colleagues* (full-text) which includes a couple of notable names on the authorship list including Dick Deth (macroepigenetics and high-fructose corn syrup) and Mady Hornig (carbohydrate digestion and the bacteria which just rolls of the tongue, Sutterella in relation to autism).

The name of the paper's game is cysteine uptake in autism, and how issues with this process may have some interesting connections to "inadequate antioxidant capacity" and onwards affecting prenatal- and postnatal epigenetic programming. I have to admit that this paper does jump around quite a bit in terms of what might impact on what so don't be surprised if I start bringing quite disparate areas into this post. I'll also say now that ultimately this is a paper of mouse models and how an old friend, autoimmuunity, might play some role in cysteine uptake. I'll stress the 'might play some role' before I progress any further.

A few descriptions first:

The amino acid cysteine has cropped up previously on this blog. Not only linked to those very important observations on sulphate (sulfate) levels in various biofluids in cases of autism but also with regards to the growing interest in glutathione (GSH) and autism as a result of cysteine being one of the building blocks of GSH and the various brain revelations published not so long ago.

Epigenetics... well, you could have a look at this post from a few months back introducing epigenetics in relation to autism. The mantra: your genome might not necessarily be your destiny just about covers the science of epigenetics and potentially how epigenetics might resolve some of the issues in the grudge match that is genes vs. environment. I've posted about this elsewhere quite recently (here).

Anyway back to the Waly paper. It is open-access but here are a few of the highlights:

• Unless I am missing something, it is not immediately clear whether this is a summary paper, an experimental-type paper or some combination of the two. After a few reads, I favour the latter option because aside from introducing the important processes involved in cysteine metabolism and epigenetics, there does appear to be some practical experimentation on various types of cell and tissue derived from animal models; in particular the C57BL/6  and SJL/J mouse models. Unfortunately no room for the BTBR Dangermouse model of autism.
• Indeed the practical experiment side of things seemed to involve a few things including: (a) extracting things like regulatory (CD4+ CD25+) T-cells from the mouse models to ascertain the expression of EAAT3, a mediator of cysteine uptake in various body sites (see here) (b) analysis of the level of GSH in the frontal cortex of said mouse models treated with or without the mercury-based preservative thiomersal (or thimerosal) which has been the focus of quite a lot of discussion over the years, and (c) analysis of the activity of methionine synthase, the enzyme that converts homocysteine to methionine, again in the cortex of thiomersal treated and untreated mice.
• A few of the results, but don't quote me on this: GSH levels in the frontal cortex of the SJL/J mice were lower than the C57BL/6 mice. This might make a little more sense if I point you towards some evidence that the SJL/J mouse has been described as quite a good model of autoimmunity, or at least slightly better than the C57BL/6 model.
• Similarly, levels of methionine synthase activity were described as lower in the SJL/J mice.
• It appears that thiomersal treatment had very little effect on GSH or methionine synthase activity results.
• The EAAT3 results, remembering that EAAT3 transports cysteine, cysteine from dietary sources, into cells partly for GSH synthesis. "Expression of EAAT3 was significantly lower in CD4+ T-cells from SJL/J mice versus C57BL6/J mice, suggesting that autoimmunity is associated with impaired capacity for cysteine uptake."

I'll admit that I have scratched my head a few times when reading this paper. The title suggests epigenetic programming to be a core part of the presented evidence but ultimately the data seems to focus more on the speculation around the mouse model differences over any experimental data on a specific epigenetic role tied to autism.

Don't get me wrong, the GSH and methionine synthase expression findings are important and I would love to see how they might compare against the BTBR mouse model of autism bearing in mind its representativeness to autism (see this paper by Pobbe and colleagues** full-text). The additional fact that thiomersal treatment seemed to have very little effect on these parameters in both mouse models is also a potentially important finding.

That being said I almost got the impression that this paper might have been better split into two manuscripts: one on the speculated mechanisms, which provide an excellent overview it has to be said, and another on the fact that C57BL/6 mice don't tend to show as many issues with cysteine, glutathione and methionine pathways as the SJL/J mouse. I caution though that this last finding might not necessarily translate into real life autism.

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* Waly M. et al. Prenatal and postnatal epigenetic programming: implications for GI, immune, and neuronal function in autism. Autism Research & Treatment. 2012
DOI: 10.1155/2012/190930

** Pobbe RL. et al. Expression of social behaviors of C57BL/6J versus BTBR inbred mouse strains in the visible burrow system. Behavioral Brain Research. 2010; 214: 443-449.