Invited reviewInvolvement of quinolinic acid in the neuropathogenesis of amyotrophic lateral sclerosis
Section snippets
Introduction to ALS
Amyotrophic lateral sclerosis (ALS) is the most common form of Motor Neuron Disease (MND). Also known as Lou Gehrig's disease, it is a fatal neuromuscular disorder characterized by the progressive loss of motor neurons in the spinal cord, brain stem, and cortex, thereby affecting the corticobulbar and corticospinal motor tracts, and nuclei of cranial nerves and ventral horn of the spinal cord (Fig. 1). Clinically, ALS produces progressive weakness, resulting in atrophy of the limb, axial, and
Introduction to the KP
The KP is the primary degradation pathway for the essential amino acid Tryptophan (TRP). TRP is an essential amino acid that cannot be synthesized by the human body, and must be obtained from the diet. Once absorbed by the body, TRP is transported around the periphery either bound to albumin (90%) or in free form, the two states existing in an equilibrium (McMenamy, 1965). Only the free form can be transported across the blood-brain barrier (BBB) by the competitive and non-specific L-type amino
Potential therapeutics for ALS
Several therapeutic agents have been tested in clinical trials in patients with ALS. Among them, riluzole was the first, and remains the only drug approved by the FDA (USA) in 1995 for treatment of ALS. The approval was based on two large placebo controlled clinical studies where riluzole decreased the rate of muscle deterioration and modestly improved the survival rate of ALS patients (Bensimon et al., 1994, Cifra et al., 2013, Lacomblez et al., 1996). Although the specific mechanism of
Hypothetical model of QUIN and KP in ALS, and KP modulators as potential ALS treatments
Based on current literature and our data, we have formulated a hypothetical model (Fig. 3) for the involvement of QUIN in the neuropathogenesis of ALS. It incorporates the ALS mechanisms of excitotoxicity, oxidative stress, mitochondrial dysfunction, inflammatory cascade, apoptosis, and autophagic progress with contributions QUIN and the KP.
We propose that targeting the KP could offer a new therapeutic opportunity in ALS, and QUIN is a forerunner for KP modulation. Elevated concentrations of
Conflict of interest
None.
Acknowledgements
The authors would like to thank Ms Stephanie RAYNER for her assistance with Fig. 3. Ms Vanessa TAN is supported by an international scholarship from Macquarie University. Prof Gilles GUILLEMIN is supported by the National Health and Medical Research Council (NHMRC) and the Australian Research Council (ARC). Prof GUILLEMIN is a recipient of the Australian Research Council Future Fellowship Award (FT120100397). Dr Nady BRAIDY is the recipient of an Alzheimer's Australia Viertel Foundation
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Cited by (33)
Indoleamine 2,3-dioxygenase
2023, Metalloenzymes: From Bench to BedsideNonheme mono- and dioxygenases
2023, Metalloenzymes: From Bench to BedsideQuinolinic acid catabolism is initiated by a novel four-component hydroxylase QuiA in Alcaligenes faecalis JQ191
2023, Environmental ResearchCitation Excerpt :QA is used for synthesizing nicotinamide adenine dinucleotide (NAD+) through the de novo synthesis in animals (Esquivel et al., 2016; Moffett and Namboodiri, 2003) and through the salvage pathways in bacteria and plants (Ashihara et al., 2005; Brickman et al., 2017, 2018; Ohashi et al., 2013). On the other hand, QA is a highly potent agonist of N-methyl-D-aspartate (NMDA) receptor, which causes peripheral inflammation and has been proved to be associated with many neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), stroke, and multiple sclerosis (MS) (Bradley et al., 2015; Esquivel et al., 2016; Guillemin, 2012; Lee et al., 2017; Moffett and Namboodiri, 2003). Furthermore, QA is also an important chemical precursor, which has a wide application in the synthesis of pesticides, chemicals and dyes etc (Gupta and Rather, 1989; Zhu et al., 2021).
C-Reactive protein and the kynurenic acid to quinolinic acid ratio are independently associated with white matter integrity in major depressive disorder
2022, Brain, Behavior, and ImmunityCitation Excerpt :However, as discussed elsewhere (Savitz, 2022), the issue is complicated by the fact that the concentration of biomarkers in the CSF do not always correlate significantly with their concentration in the brain parenchyma (Gadad et al., 2021). Thus, although there is no consensus regarding the neurophysiological significance of serum measures of KP metabolites, a growing number of studies report correlations between these metabolites and brain structure or function (Chen et al., 2021; Comai et al., 2022; DeWitt et al., 2018; Doolin et al., 2018; Lee et al., 2017; Meier and Savitz, 2022; Paul et al., 2022; Poletti et al., 2018; Savitz, 2020). Ultimately, experimental studies that manipulate the KP will be needed to resolve this question.
Chromatographic measurement of 3-hydroxyanthranilate 3,4-dioxygenase activity reveals that edaravone can mitigate the formation of quinolinic acid through a direct enzyme inhibition
2022, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :ACMS can be then converted to picolinic acid (PA) by another enzymatic reaction or undergo a spontaneous, non-enzymatic cyclization which produces the neurotoxic metabolite quinolinic acid (QUIN, see Fig. 1). High levels of QUIN have been detected in both serum and cerebrospinal fluid in several inflammatory diseases and infections, as well as in the neuronal and microglial cells of the motor cortex and spinal cords of patients with amyotrophic lateral sclerosis (ALS) [2,3]. Moreover, QUIN is capable of inducing superoxide dismutase 1 (SOD1) in astrocytes, which could intensify the deleterious effects associated with mutant SOD1 in ALS [4].
Advantages of brain penetrating inhibitors of kynurenine-3-monooxygenase for treatment of neurodegenerative diseases
2021, Archives of Biochemistry and BiophysicsCitation Excerpt :Similarly to Huntington's and Alzheimer's diseases, Parkinson's disease is a protein misfolding disorder. Indeed, misfolding and aggregation of α-synuclein, which is the major component of Lewy bodies, is associated with Parkinson's pathogenesis [45,46]. In a manner similar to tau, QUIN has been found to seed aggregation of α-synuclein [47], which may have ramifications on Parkinson's pathogenesis.
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Co-first authorship (Lee, and Tan).