Tryptophan, what have you been doing?

August 29, 2012

The University of Groningen where I currently study has formulated three key research areas that are meant as a strategic aim in order to distinguish itself from other universities. One of these research areas is called “Healthy Ageing”. This week the scientific journal PNAS will publish an interesting article on work by Dr. Ellen Nollen and coworkers in which they describe how the depletion of a certain gene leads to higher tryptophan levels and seems to protect C. elegans worms from protein aggregate-related disease. Since protein aggregates are hold responsible for Alzheimer and Parkinson disease in humans and not a lot is known about the related protein metabolism, this paper indicates some new potential therapeutic targets and fits perfectly into the university’s aim to promote research on “Healthy Ageing”.

As this paper indicates that high levels of thryptophan might have a protective effect against protein aggregate-related diseases I considered it interesting to look into it a little bit deeper. The gene that is central within this research is called tryptophan 2,3-dioxygenase (tdo-2) and encodes the enzyme TDO-2 which is responsible for the digestion of the essential amino acid tryptophan. During their studies the researchers from the Netherlands, Germany, and France found that genetic suppression of tdo-2 (also called knockdown) leads to inhibition of the tryptophan metabolism and thereby to higher levels of this amino acid in the tissues of the worms which were the labrats-substitutes here. Deciphering a metabolic pathway is very nice, but what makes van der Groot’s et al. results even more interesting is the fact that a longer lifespan of the worms was observed upon tdo-2 knockdown. It also proved to be effective to supply excess amounts of tryptophan and leave the tdo-2 gene “switched on”. Since in general C. elegans is regarded as a good model organisms for age-related diseases such as Parkinson or Alzheimer, in the following let us have a closer look at the study and its results.

The worms which were part of this study actually suffered from the expression of alpha-synnuclein known for its protein aggregation promoting behaviour. High levels of this compounds actually lead to less motility of the worms and expressed in the unit body bends/minute. Suppressing tdo-2 with RNAi considerably extended the time period within the worms lives with a high motility rate. According to the researchers this indicates suppressed effects of alpha-synuclein.

As metabolic networks are important in biology the next question asked as whether an up- or downstream (concerning the location of tdo-2) element was responsible for the observed effects. All the genes mentioned in Fig. 1 were knocked down in combination with or without tdo-2 expression and it was observed that knock-downs of downstream genes had no or only a very small effect on worm motility. Therefore the levels of tryptophan seemed to be the key to the observed effects.

Fig. 1: TDO-2 related metabolic pathway. 

However and as depicted in the above figure tryptophan is also a part of the neurotransmitter serotonin synthesizing pathway. Serotonin levels are currently a prime element in the understanding of Alzheimer disease and are also used in therapeutic approaches. A significant element of Nollen’s and her colleagues’ work is, however, that they prove that serotonin has nothing to do with the observed motility and lifespan effects. Knocking down the tph-1 gene in combination with tdo-2 does not significantly change the worms abilities to move. Summing up, all conducted knock-downs during this study therefore lead to the conclusion that the TDO-2 enzyme and (when it is suppressed) higher tryptophan levels are responsible for the increased mobility and decreased alpha-synuclein toxicity. This point was further stressed by the addition of tryptophan to the diet of worms which did express TDO-2 (Fig. 2). In a dose dependent manner tryptophan compensates for alpha-synuclein toxicity. 

Fig. 2: Raised tryptophan levels suppress alpha-nuclein toxicity also in the absence of a tdo-2 knockdown.

Now it starts to become interesting: What does tryptophan do? How does it prevent protein aggregation on a molecular basis? Does it regulate some yet unknown biochemical pathways? Sadly enough the authors stay very brief on these points, either because they do not know more themselves yet or because another publication in Nature or Science is waiting in the future. What they say is that they do not expect tryptophan to be directly responsible for the observed effects, but this amino acid (or its derivates) probably plays a role on other biochemical pathways or their signalling molecules. Nevertheless this work proves that a lot of knowledge about protein aggregate-related diseases still remains in the dark. It also opens up possibilities to study the observed effects in mammals since the tdo-2 gene and its enzyme product is evolutionarily extremely well conserved. TDO-2 is one of the proteins that links us with C. elegans worms. To what extend the tryptophan metabolism plays a role in human age-related diseases such as Alzheimer and Parkinson is a question that many research groups will work on in the future.

van der Groot AT et al., Delaying aging and aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. Proceedings of the National Academy of Sciences of the United States of America, published online before print on August 27th 2012, accessed on August 29th 2012. 

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