Consequences of KP manipulation. KP metabolites and enzymatic steps are indicated in black, whereas the key KP enzymes TDO, KMO, and KATs are indicated in purple. The metabolites 3-HK and QUIN are neurotoxic (as indicated by red arrows), whereas KYNA and TRP are neuroprotective (as indicated by green arrows). Inhibition of TDO results in increased TRP levels, and either TDO or KMO inhibition leads to a reduction in the 3-HK/KYNA ratio (highlighted in blue). The enzyme 3-hydroxyanthranilic acid dioxygenase is not present in flies, and thus QUIN is not synthesized.
Lab-based study discovers way of ‘reversing’ symptoms. The researchers have demonstrated that genetic and pharmacological approaches can be used to lower levels of toxic metabolites in the nervous system and thereby alleviate several symptoms of neurodegeneration. The newly published research utilized the common lab fruit fly Drosophila melanogaster in order to explore the role of specific metabolites in the kynurenine pathway that cause loss of nerve cells in models of Alzheimer’s, Parkinson’s, and Huntington’s diseases.
Past studies by the Leicester team and others have shown some of these metabolites are toxic to nerve cells, and their levels are increased in these diseases. In the past the researchers have found that they can use genetic approaches to inhibit (or “mute”) the activity of 2 critical enzymes in this pathway – TDO and KMO – which lowers levels of the toxic metabolites and reduces nerve cell loss in a fruit fly model of Huntington’s disease. In the current study inhibiting these two enzymes improves “symptoms” in flies because of increased levels of a “protective” kynurenine pathway metabolite known as kynurenic acid which counteracts the effects of the toxic metabolites.
Prof. Giorgini said: “There is a fine balance between levels of “good” and “bad” metabolites that occurs in the kynurenine pathway. In disease, it shifts towards the “bad,” and by inhibiting TDO or KMO, we shift it back to “good.” Eg, we find that if we inhibit either TDO or KMO in Huntington’s flies we reduce loss of neurons. In Alzheimer’s or Parkinson’s flies we see extension of the shortened lifespan exhibited by these flies, and we also reverse the defects they have in movement. We have even used a drug-like chemical to inhibit TDO and found that this also alleviates ‘symptoms’.”
Dr Breda said: “There is considerable interest in developing drugs that ‘turn down’ these enzymes, so our hope is that our work could lead to drugs to treat these devastating disorders in the future.” Professor Giorgini added: “…our next step is to validate our work in mammalian models and ultimately to see if such drugs could be helpful to patients in clinical trials.”
Commenting on the research Claire Bale, Head of Research Communications at Parkinson’s UK, says, “Parkinson’s is a progressive neurological brain condition, with symptoms emerging when 70% of nerve cells in the brain have been lost.
“This research which focuses on protecting brain cells, such as those lost in Parkinson’s, by targeting proteins in the kynurenine pathway, could provide a turning point in the fight against this condition – which currently has no cure.
http://www.eurekalert.org/pub_releases/2016-04/uol-naa042516.php
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