Thioredoxin... a new 'diagnosis indicator' for autism?

My name's Buttercup. You've
met Baron von Shush.

"Our study demonstrated that serum TRX [thioredoxin] levels were associated with ASD [autism spectrum disorder], and elevated levels could be considered as a novel, independent diagnosis indicator of ASD." So was the conclusion reported by Qing-biao Zhang and colleagues [1] looking at serum levels of TRX in 80 children diagnosed with an ASD compared against "100 sex and age matched typically developing children".

I'll freely admit that I was not even aware of thioredoxin (TRX) before reading this study; although a quick trawl through some of the research literature on this protein that "act as antioxidants by facilitating the reduction of other proteins by cysteine thiol-disulfide exchange" (thank you Wikipedia) hints that I should have been. Quite a good [peer-reviewed] overview of TRX can be found in the paper by Arnér & Holmgren [2] and in particular, describing their role in the process of reducing oxidative stress similar to another compound of interest to this blog: glutathione.

Zhang and colleagues reported significantly higher median serum levels of TRX in their participants with autism compared to asymptomatic controls. Further, that the severity of autism  - as measured using the CARS - might also be linked to TRX levels, and "the optimal cut-off value of serum TRX levels as an indicator for auxiliary diagnosis of autism was projected to be 10.6ng/ml". I might add that such results should not be translated as serum levels of TRX higher than 10.6 ng/ml = autism exclusively, as per other research looking at elevated levels of TRX in other conditions [3].

This is not the first time however that TRX has been studied with autism in mind. The paper by Yusra A Al-Yafee and colleagues [4] (open-access) looking at "sulfur-dependent detoxification mechanisms" in relation to the autism spectrum noted that alongside aberrant values for glutathione (yes, quite consistently so) in their autistic cohort, elevated levels of TRX and related thioredoxin reductase (TrxR) were also detected compared with controls. They stated: "the recorded raised levels of Trx, TrxR and Prxs [peroxidoxins] of the present study could be related to... previous work... which they proved that Saudi autistic children are under H2O2 stress due to over expression of SOD and a slightly lower activity of catalase." Interestingly, this group also suggested that TRX and glutathione parameters might also have some legs when it comes to their usefulness "as diagnostic biomarkers of autism."

Oxidative stress and autism is a research area in the ascendancy. With links being made to the gastrointestinal (GI) issues quite commonly reported alongside a diagnosis of autism (see here) and some really quite interesting work talking about oxidative stress potentially inducing mitochondrial issues in autism (see here), some important correlations are being made. My recent discussions including the paper by Main and colleagues [5] (open-access) suggesting that: "children with autism are more sensitive to necrosis caused by oxidative and nitrosative stress than their non-autistic siblings" adds to the intrigue, as does a little study about broccoli extracts recently...

Of course, quite a lot more replicative work is required, also including more focus on the hows and whys of issues with redox regulation related to autism. But more and more, oxidative stress is taking a place among quite a few other issues detected in at least some cases of autism [6].

Music to close: Queenie Eye by Paul McCartney.

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[1] Zhang QB. et al. Thioredoxin: A novel, independent diagnosis marker in children with autism. Int J Dev Neurosci. 2014 Nov 26. pii: S0736-5748(14)00191-9.

[2] Arnér ES. & Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000 Oct;267(20):6102-9.

[3] Yamada Y. et al. Elevated serum levels of thioredoxin in patients with acute exacerbation of asthma. Immunol Lett. 2003 Apr 3;86(2):199-205.

[4] Al-Yafee YA. et al. Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia. BMC Neurol. 2011 Nov 4;11:139.

[5] Main PA. et al. Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress. Mutagenesis. 2013 Jul;28(4):475-84.

[6] Rossignol DA, Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Frontiers in Physiology 2014;5:150. doi:10.3389/fphys.2014.00150.

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Zhang QB, Gao SJ, & Zhao HX (2014). Thioredoxin: A novel, independent diagnosis marker in children with autism. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience PMID: 25433158