Tryptophan 2,3-dioxygenase as a potential target for the treatment of neurodegenerative disorders

Abstract

The kynurenine pathway is crucial for the metabolism of tryptophan in mammals. It has been suggested that a dysregulation of the kynurenine pathway plays an important role in the development of neurodegenerative diseases. The first and rate-limiting step of the kynurenine pathway of tryptophan degradation is catalysed by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), which leads to the formation of N-formylkynurenine, which in turn leads to the formation of kynurenine. Kynurenine-3-monooxygenase catalyses the synthesis of kynurenine’s neuroactive metabolites: the neurotoxic 3-hydroxykynurenine and quinolinic acid and the neuroprotective kynurenic acid. There is evidence that an imbalance between these three metabolites could potentially lead to neurodegeneration, which could cause neurodegenerative diseases. Recently several studies have highlighted the therapeutic potential of the enzyme TDO. Therefore, TDO as a therapeutic target in Parkinson’s disease, Huntington’s disease and Alzheimer’s disease is reviewed. Inhibition of the kynurenine pathway was found to be neuroprotective in several models of Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease. Particularly, inhibition of TDO was found to be neuroprotective in fruit fly and mice models of these neurodegenerative diseases. It is hypothesized that inhibition of TDO is neuroprotective by restoring the balance between the neuroactive metabolites of the kynurenine pathway. Furthermore, the therapeutic potential of IDO and kynurenine-3-monooxygenase is highlighted. Even though more research is needed to further validate TDO as a potential target, it shows great potential as a target for the treatment of neurodegenerative disorders.