Serotonin - melatonin (and the in-betweeners) linked to autism

The paper by Pagan and colleagues [1] (open-access) looking at "serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD [autism spectrum disorder] and their relatives" set the old grey-pink matter into action recently. Not only because I have some real interest in the starting material for these compounds - the aromatic amino acid known as tryptophan - but because this research group included some quite important analysis of the enzymes involved in the reaction from serotonin to melatonin with autism in mind.

Just before heading into the paper and the details, I'm gonna draw your attention to the picture shown to the right (hand drawn by yours truly) which was originally included in a blog post on something called 5-hydroxytryptophan (5-HTP). As you can see, the source material tryptophan eventually cascades down into various other compounds with serotonin and melatonin in mind. I might add that this is not the only metabolic fate of tryptophan as, for example, per another important compound set: the kynurenine pathway again talked about on this blog.

Serotonin (5-HT) for those who might not know is a neurotransmitter that represents one of the 'S' in the class of medicines called SSRIs hinting at its relationship to mood regulation among other things. Melatonin by contrast has quite an important role in functions like sleep; although, as has been previously mentioned on this blog, melatonin might be quite the molecular handyperson (see here). Both serotonin and melatonin have some history when it comes to autism research and practice (see here for example).

N-acetylserotonin (NAS) is a slightly less well-known compound when it comes to autism. A quick trawl of PubMed using the search term 'N-Acetylserotonin autism' came up with two other entries at the time of writing. Granted both the Anderson-Maes [2] and Carter and colleagues [3] make for interesting reading for different reasons, but there does seem to be a dearth of research on the possibility of a role for NAS for at least some autism.

Now, back to the Pagan paper and a few pointers even though it is open-access:

• The hypothesis: "that (i) the intermediate NAS might also be altered, (ii) alterations of the serotonin-NAS–melatonin pathway might constitute a possible biomarker for a subgroup of individuals with ASD and that (iii) they would be associated with specific clinical profiles."
• Whilst avoiding foods high in tryptophan and/or serotonin such as bananas and chocolate, morning blood samples were provided by "278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls" and various parts of the sample assayed for serotonin, melatonin and NAS. The analytical weapons of choice were HPLC (albeit with a rather antiquated method by today's mass spec / NMR standards) and ELISA among other things. A small number of urine samples were also collected and analysed for 6-Sulfatoxymelatonin.
• Results: on the whole, those with autism presented with "elevated whole-blood serotonin" whilst "Plasma melatonin was significantly decreased in individuals with ASD and their relatives compared with controls." These are not surprising results given the research history in this area. 
• With slightly more novelty: "the intermediate metabolite NAS, measured in blood platelets, was found to be significantly elevated in individuals with ASD and their relatives compared with controls." Further such elevations in platelet NAS "strongly correlated" with the plasma melatonin findings noted in cases of autism. 
• There was potentially also something to see when the results were pooled together in terms of discriminating autism from not-autism but I'll leave it up to you to decide how well their biomarkers functioned.
• Bearing in mind my diagram shown above, the increase in serotonin, increase in NAS but decrease in melatonin might provide some important information about where there may be a metabolic 'block'. In this respect, the authors' analysis of "two enzymes, AANAT [Aralkylamine N-acetyltransferase] and ASMT [N-Acetylserotonin O-methyltransferase] known to form protein complexes with 14-3-3 scaffolding proteins" is also important. Actually, authors looked at 14-3-3 in platelets and reported it/them: "significantly decreased in patients with ASD." Previous work from this group [4] had indicated that ASMT activity to be lower in cases of autism; thus suggesting that problems with this enzyme or the availability of this enzyme converting NAS to melatonin might for example, account for the lower melatonin findings.

I've gone on a little bit in this post but hope that you can see the logic in doing so. Metabolic pathways when it comes to human physiology are pretty complex things affected by all manner of variables including things like enzyme function and the availability of those all-important cofactors (see here for some chatter about BH4 for example). Pagan et al have done a good preliminary job of stitching together some important compounds with autism in mind and particularly their findings in relation to NAS. I personally am looking forward to seeing some independent replication of these findings and perhaps onwards, a little more analysis of some other tryptophan derivatives [5] potentially important to [some] autism...

A little music to close: Mark Ronson - Uptown Funk.

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[1] Pagan C. et al. The serotonin-N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders. Translational Psychiatry. 2014. November 11.

[2] Anderson G. & Maes M. Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites, Immuno-inflammation, Autoimmunity and the Amygdala. Curr Neuropharmacol. 2014 Mar;12(2):148-67.

[3] Carter MD. et al. Quantitation of melatonin and n-acetylserotonin in human plasma by nanoflow LC-MS/MS and electrospray LC-MS/MS. J Mass Spectrom. 2012 Mar;47(3):277-85.

[4] Melke J. et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry. 2008 Jan;13(1):90-8.

[5] Anderson RJ. et al. Identification of indolyl-3-acryloylglycine in the urine of people with autism. J Pharm Pharmacol. 2002 Feb;54(2):295-8.

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Pagan C, Delorme R, Callebert J, Goubran-Botros H, Amsellem F, Drouot X, Boudebesse C, Le Dudal K, Ngo-Nguyen N, Laouamri H, Gillberg C, Leboyer M, Bourgeron T, & Launay JM (2014). The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders. Translational psychiatry, 4 PMID: 25386956