Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis.

Autor:	Fifita JA; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia., Chan Moi Fat S; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia., McCann EP; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia., Williams KL; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia., Twine NA; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.; Australian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organization, Health & Biosecurity Flagship, Sydney, NSW, Australia., Bauer DC; Australian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organization, Health & Biosecurity Flagship, Sydney, NSW, Australia.; Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.; Applied BioSciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia., Rowe DB; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.; Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia., Pamphlett R; Discipline of Pathology, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.; Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.; Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia., Kiernan MC; Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.; Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Tan VX; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia., Blair IP; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia., Guillemin GJ; Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Jun 14; Vol. 12, pp. 701550. Date of Electronic Publication: 2021 Jun 14 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.701550
Abstrakt:	The essential amino acid tryptophan (TRP) is the initiating metabolite of the kynurenine pathway (KP), which can be upregulated by inflammatory conditions in cells. Neuroinflammation-triggered activation of the KP and excessive production of the KP metabolite quinolinic acid are common features of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In addition to its role in the KP, genes involved in TRP metabolism, including its incorporation into proteins, and synthesis of the neurotransmitter serotonin, have also been genetically and functionally linked to these diseases. ALS is a late onset neurodegenerative disease that is classified as familial or sporadic, depending on the presence or absence of a family history of the disease. Heritability estimates support a genetic basis for all ALS, including the sporadic form of the disease. However, the genetic basis of sporadic ALS (SALS) is complex, with the presence of multiple gene variants acting to increase disease susceptibility and is further complicated by interaction with potential environmental factors. We aimed to determine the genetic contribution of 18 genes involved in TRP metabolism, including protein synthesis, serotonin synthesis and the KP, by interrogating whole-genome sequencing data from 614 Australian sporadic ALS cases. Five genes in the KP ( AFMID, CCBL1, GOT2, KYNU, HAAO ) were found to have either novel protein-altering variants, and/or a burden of rare protein-altering variants in SALS cases compared to controls. Four genes involved in TRP metabolism for protein synthesis ( WARS ) and serotonin synthesis ( TPH1, TPH2, MAOA ) were also found to carry novel variants and/or gene burden. These variants may represent ALS risk factors that act to alter the KP and lead to neuroinflammation. These findings provide further evidence for the role of TRP metabolism, the KP and neuroinflammation in ALS disease pathobiology. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Fifita, Chan Moi Fat, McCann, Williams, Twine, Bauer, Rowe, Pamphlett, Kiernan, Tan, Blair and Guillemin.)
Databáze:	MEDLINE
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