The kynurenine pathway and neurodegenerative disease

Abstract

Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been closely linked to the pathogenesis of several neurodegenerative diseases. Tryptophan is an essential amino acid required for protein synthesis, and in higher eukaryotes is also converted into the key neurotransmitters serotonin and tryptamine. However, in mammals >95% of tryptophan is metabolized through the KP, ultimately leading to the production of nicotinamide adenosine dinucleotide (NAD + ). A number of the pathway metabolites are neuroactive; e.g. can modulate activity of several glutamate receptors and generate/scavenge free radicals. Imbalances in absolute and relative levels of KP metabolites have been strongly associated with neurodegenerative disorders including Huntington's, Alzheimer's, and Parkinson's diseases. The KP has also been implicated in the pathogenesis of other brain disorders (e.g. schizophrenia, bipolar disorder), as well as several cancers and autoimmune disorders such as HIV. Pharmacological and genetic manipulation of the KP has been shown to ameliorate neurodegenerative phenotypes in a number of model organisms, suggesting that it could prove to be a viable target for the treatment of such diseases. Here, we provide an overview of the KP, its role in neurodegeneration and the current strategies for therapeutic targeting of the pathway.

Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course

“…Tryptophan metabolism through the kynurenine pathway has been associated with autoimmune and neurodegenerative diseases 33, 34. Pro‐inflammatory cytokines stimulate indoleamine 2,3‐dioxygenase, the first enzyme in the kynurenine pathway.…”

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

“…Impairments in KP metabolism have been linked to several neurodegenerative disorders, and in particular to the pathogenesis of HD (37). Notably, increased levels of 3-HK and QUIN have been measured in the neostriatum and cortex of patients with early stage HD (15), and these changes are associated with an up-regulation of IDO1 transcription (38) and a reduction in the activity of KAT, which is critical for KYNA synthesis (17).…”

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease

“…Dysregulation of KP enzymes has been implicated in a variety of conditions, and changing levels of various neuroactive KP metabolites have been correlated with alterations in brain function in the context of affective disorders, cognition, neuroinflammatory disorders and neurodegeneration Maddison and Giorgini, 2015;Stone and Darlington, 2013). Evidence of the KP's involvement largely comes from animal models and humans, but few studies have been conducted with optimized molecules with suitable properties for longterm dosing, a necessary step to evaluate the contribution of specific enzymes to disease progression (Justinova et al, 2013;Kozak et al, 2014).…”

“…The kynurenine (Kyn) pathway (KP) is the major catabolic pathway for the degradation of tryptophan, and several KP metabolites have important functions in the context of brain function and in the modulation of the immune system Maddison and Giorgini, 2015;Stone and Darlington, 2013). Kyn catabolism is mediated by multiple enzymes, which are differentially expressed in tissues and cell types.…”

“…Finally, kynureninase converts Kyn to anthranilic acid (AA), which can be further metabolized to generate 3-OH-AA (Figure 1a). Several of the KP metabolites have been shown to be neuroactive and alterations in their levels has been associated with a variety of brain disorders, most notably in the context of neurodegeneration, cognition and affective disorders Maddison and Giorgini, 2015;Stone and Darlington, 2013 ). Adding further to the complexity of KP signaling, multiple KP metabolites can cross the BBB from the periphery via the action of amino acid transporters expressed in the brain vascular endothelium.…”