Kynurenine Pathway Metabolites as Biomarkers for Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) currently lacks a robust and well-defined biomarker that can 1) assess the progression of the disease, 2) predict and/or delineate the various clinical subtypes, and 3) evaluate or predict a patient's response to treatments. The kynurenine Pathway (KP) of tryptophan degradation represent a promising candidate as it is involved with several neuropathological features present in ALS including neuroinflammation, excitotoxicity, oxidative stress, immune system activation and dysregulation of energy metabolism. Some of the KP metabolites (KPMs) can cross the blood brain barrier, and many studies have shown their levels are dysregulated in major neurodegenerative diseases including ALS. The KPMs can be easily analyzed in body fluids and tissue and as they are small molecules, and are stable. KPMs have a Janus face action, they can be either or both neurotoxic and/or neuroprotective depending of their levels. This mini review examines and presents evidence supporting the use of KPMs as a relevant set of biomarkers for ALS, and highlights the criteria required to achieve a valid biomarker set for ALS.

Keywords: amyotrophic lateral sclerosis; biomarker development; kynurenine pathway; motor neuron disease; neurodegeneration; neuroinflammation and neurodegeneration; tryptophan.

FIGURE 1

The Kynurenine Pathway and its downstream pathways of Serotonin/Melatonin, BH4, Glycolysis, and NAD+. Tryptophan is converted into serotonin and melatonin, that regulate mood and sleep. The tetrahydrobiopterin (BH4) pathway interacts with the KP in three ways, (1) the sharing of the enzyme TPH that degrades tryptophan, (2) the inhibition of a key BH4 pathway enzyme, sepiapterin reductase, (3) both BH4 and KP are induced by inflammatory cytokines. Tryptophan also feeds into the glycolysis cycle via ACMS, affecting ATP production. Finally, the KP is the de novo synthesis pathway of NAD+ which is associated with cellular energy, repair and fatigue. The key KPMs are bolded, neurotoxic metabolites represented in red, neuroprotective metabolites in green, and dual functioning in blue.