Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway

Abstract

Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into a certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise to the treatment. Peripheral biomarkers are to play a central role for tailoring a personalized therapeutic plan for patients who suffered from neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, among others. Nevertheless, the use of biomarkers in clinical practice is still underappreciated and data presented in biomarker research for clinical use is still uncompelling, compared to the abundant data available for drug research and development. So is the case with kynurenines (KYNs) and the kynurenine pathway (KP) enzymes, which have been associated with a wide range of diseases including cancer, autoimmune diseases, inflammatory diseases, neurologic diseases, and psychiatric disorders. This review article discusses current knowledge of KP alterations observed in the central nervous system as well as the periphery, its involvement in pathogenesis and disease progression, and emerging evidence of roles of microbiota in the gut-brain axis, searching for practical peripheral biomarkers which ensure personalized treatment plans for neurodegenerative diseases.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; biomarkers; kynurenines; multiple sclerosis; neurodegenerative disease; personalized medicine; tryptophan.

Figure 1

Tryptophan metabolism and the kynurenine pathway. The kynurenine pathway (KP) is the main degradation route of tryptophan (TRP) metabolism producing the end-product nicotinamide adenine dinucleotide (NAD). The indoleamine-2,3-dioxygenase-1 and 2 (IDO-1 and IDO-2), and the tryptophan 2,3-dioxygenase (TDO) (1) are the first rate-liming enzymes that convert the l-TRP to N-formyl-l-kynurenine. N-formyl-l-kynurenine is converted by formamidase (2) to l-kynurenine (l-KYN) (gray box). l-KYN is metabolized into various bioactive compounds: the neuroprotective metabolites are kynurenic acid and picolinic acid (green boxes), while the neurotoxic ones are 3-hydroxy-l-kynurenine (3-HK) and quinolinic acid (red boxes). The main enzymes of the KP are following: 1: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 1 and 2 (IDO-1 and IDO-2), 2: formamidase, 3: kynurenine aminotransferases (KATs), 4: kynurenine-3-monooxygenase (KMO), 5: kynureninase, 6: non-specific hydroxylation, 7: 2-amino-3-carboxy-muconate-semialdehyde decarboxylase, 8: 3-hydroxyanthranilate oxidase, 9: quinolinic acid phosphoribosyltransferase.

Figure 2

The central nervous system and periphery sequestrated by the blood-brain-barrier and the microbiota-gut-brain axis. The impermeable peripheral metabolites are sequestrated from the central nervous system (CNS) by the blood-brain barrier (BBB). The gastrointestinal microbiota changes the composites of the peripheral metabolites. Tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (3-HK) are permeable, but kynurenic acid (KYNA) and quinolinic acid (QUIN) are impermeable to the BBB. When the integrity of the BBB is compromised such as in inflammation, the microbiota influences the brain function and thus behavior through the microbiota-gut-brain axis. TDO: tryptophan 2,3-dioxygenas; IDO: indoleamine 2,3-dioxygenase.