Tuesday, 25 August 2015

MOCOS: a new candidate for autism research

I'll freely admit that until reading the paper by François Féron and colleagues [1] (open-access available here) I had never heard of MOCOS (MOlybdenum COfactor Sulfurase) before.

Described as "an enzyme of the purine metabolism that sulfurates the molybdenum cofactor, thus allowing the two downstream enzymes—xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX1)—to be active", researchers reported that in nasal stem cells provided by a small group of adults diagnosed with an autism spectrum disorder (ASD), MOCOS was down-regulated compared with analyses of similar cells from asymptomatic controls. They concluded that differences related to MOCOS might be important: "likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders."

I'm intrigued.

The Féron paper is open-access but a few details might be useful:

  • Eleven participants diagnosed with autism (autism spectrum disorder, ASD) were included for study. Interestingly, DSM-5 diagnostic criteria were used to confirm the presence of ASD. Age and gender matched asymptomatic (for autism) controls were also used. As per the supplementary information included with the main article (see here), the authors characterised their participant group pretty well from various different angles.
  • A nasal biopsy was performed on participants in order to extract "nasal olfactory stem cells" based on a previously published technique [2]. Again, it's new news to me that you can get stem cells from the nose but apparently the "olfactory epithelium is also a nervous tissue that produces new neurons every day to replace those that are damaged by pollution, bacterial of viral infections. This permanent neurogenesis is sustained by progenitors but also stem cells residing within both compartments of the mucosa, namely the neuroepithelium and the underlying lamina propria."
  • Based on a "non-hypothesis-driven approach" Féron et al set about looking for "transcriptome anomalies" between the groups. Alongside other potentially important differences they stumbled across MOCOS in relation to their autism cohort and decided to look-see whether this might have some impact on cerebral functions using a classical worm model - Caenorhabditis elegans (C. elegans). A "genetic ablation of mocs-1 (the MOCOS ortholog)" engineered into the worm induced "an alteration of the response to oxidative stress and is responsible for abnormal neurotransmission phenotypes." Human cell studies confirmed this data.

Despite the small participant group, the MOCOS findings might carry some weight in view of some of the other 'dysregulated' genes that turned up with the ASD group in mind. So: "9 out of these 156 genes—ADAM23, CADM1, FOS, FOSB, JAG1, MEST, OXTR, SFRP1 and XIST—have been previously associated with ASD." You might note the mention of OXTR in that list, denoting the oxytocin receptor gene bearing in mind the cautious history in that area. That also pathway analysis of the genes differentially regulated in the autism group "identified developmental disorders and gastrointestinal diseases as two of the most represented categories associated with these genes" adds to the interest, bearing in mind the term 'over-represented' when it comes to bowel issues and autism (see here).

The suggestion that "MOCOS misexpression increases sensitivity to oxidative stress" is also an important part of the Féron findings. Oxidative stress and autism has quite a bit of peer-reviewed research history (see here for example) particularly in areas such as glutathione metabolism (see here) albeit not universally [3]. It's not beyond the realms of possibility that MOCOS may indeed be a contributory factor to such issues being present in some cases.

Further work is required in this area to corroborate the Féron data using larger participant numbers for example. With that in mind, I'll be keeping my eye open for more work on MOCOS and autism and whether it lives up to its 'new player' status...

Music: Weezer and Undone.

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[1] Féron F. et al. Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Mol Psychiatry. 2015 Aug 4.

[2] Girard SD. et al. Isolating nasal olfactory stem cells from rodents or humans. J Vis Exp. 2011 Aug 22;(54). pii: 2762.

[3] Durieux AM. et al. Cortical and subcortical glutathione levels in adults with autism spectrum disorder. Autism Res. 2015 Aug 20.

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ResearchBlogging.org Féron F, Gepner B, Lacassagne E, Stephan D, Mesnage B, Blanchard MP, Boulanger N, Tardif C, Devèze A, Rousseau S, Suzuki K, Izpisua Belmonte JC, Khrestchatisky M, Nivet E, & Erard-Garcia M (2015). Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Molecular psychiatry PMID: 26239292