Friday 23 November 2012

Stop that phenylalanine now!

I'm going slightly off-piste with this post not strictly related to autism; however remaining true to my interest in all things amino acids, and in particular one of those most interesting aromatic amino acids, phenylalanine.

Phenylalanine @ Wikipedia
A few months back Chemistry World carried a very interesting article by Jon Evans* on how the amino acid phenylalanine might very well have the capacity to form amyloid-like fibrils classically related to conditions like Alzheimers disease. The article was based on this study by Adler-Abramovich and colleagues** which reported on a few pretty important observations.

I've done amyloid or rather amyloid precursor protein (in relation to autism) on this blog before (see here). Fibrils as their name suggests, are fibre-like structures. Without trying to plagiarise the article or study, a few points are worth noting:

  • The starting point was the metabolic condition phenylketonuria (PKU), probably the most famous of the inborn errors of metabolism.
  • PKU... the problems with metabolising phenylalanine as a result of issues with phenylalanine hydroxylase leads to a build up of the amino acid which has some particularly nasty effects on the developing body and brain. Said phenylalanine levels normally controlled by lifetime dietary restriction of phenylalanine but also potentially another intervention (BH4).
  • Adler-Abramovich et al observed that phenylalanine in solution tended to 'clump' together forming something that looked like amyloid-like fibrils. Further when such phenylalanine fibrils were added to cell lines, the fibrils showed some degree of toxicity. Even further, rabbits injected with said fibrils started to generate antibodies against them. Finally, after imaging the phenylalanine fibrils, there was a match between what they saw in the laboratory and what they saw in an engineered mouse model of PKU and indeed in real people diagnosed with PKU.
  • Ipso facto: phenylalanine can form amyloid-like fibrils and such fibrils might account for the tissue damage observed in PKU.

I admit to being really quite excited about this work. Modern science knows quite a bit about PKU following the very astute observations made by Dr. Asbjørn Følling. One area however that has always required a little more study was exactly how the build-up of phenylalanine caused the problems that it does; maybe part of that question has been answered with this work.

My mind also goes back to those other aromatic amino acids like tryptophan and tyrosine and whether similar fibrils could be formed from these compounds. The answer, according to the published scientific literature so far, is a very possible yes; as per studies like this one from Cecchini and colleagues*** although quite a lot of the investigations in this area goes well above my state of knowledge.

So, once again amino acids do their stuff. It makes you wonder whether Alzheimer's disease, at least some cases, might also reflect issues with phenylalanine. Logically also whether interventions like a low phenylalanine diet or even BH4 supplementation (see here) might reflect possible areas of intervention requiring much further study?

To finish, I'm sure many of you had the same 'could try harder' reports from school as I did when I was a kid. But to get something like this.... from your Dad?


* Evans J. Anti-social amino acids gang up. Chemistry World. August 2012.

** Adler-Abramovich L. et al. Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nat Chem Biol. 8: 701-706.

*** Cecchini P. et al. The role of tryptophan in protein fibrillogenesis: relevance of Trp7 and Trp14 to the amyloidogenic properties of myoglobin. PEDS. 2012; 25: 199-203.

---------- Adler-Abramovich L, Vaks L, Carny O, Trudler D, Magno A, Caflisch A, Frenkel D, & Gazit E (2012). Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nature chemical biology PMID: 22706200

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