Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis
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 m...
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Frontiers Media S.A.
2021-06-01
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Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.701550/full |
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doaj-10afac3979ec4c8fb35c574b87ed2308 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jennifer A. Fifita Sandrine Chan Moi Fat Emily P. McCann Kelly L. Williams Natalie A. Twine Natalie A. Twine Denis C. Bauer Denis C. Bauer Denis C. Bauer Dominic B. Rowe Dominic B. Rowe Roger Pamphlett Roger Pamphlett Roger Pamphlett Matthew C. Kiernan Matthew C. Kiernan Vanessa X. Tan Ian P. Blair Gilles J. Guillemin |
spellingShingle |
Jennifer A. Fifita Sandrine Chan Moi Fat Emily P. McCann Kelly L. Williams Natalie A. Twine Natalie A. Twine Denis C. Bauer Denis C. Bauer Denis C. Bauer Dominic B. Rowe Dominic B. Rowe Roger Pamphlett Roger Pamphlett Roger Pamphlett Matthew C. Kiernan Matthew C. Kiernan Vanessa X. Tan Ian P. Blair Gilles J. Guillemin Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis Frontiers in Immunology sporadic amyotrophic lateral sclerosis (SALS) whole-genome sequence (WGS) tryptophan kynurenine pathway (KP) serotonin |
author_facet |
Jennifer A. Fifita Sandrine Chan Moi Fat Emily P. McCann Kelly L. Williams Natalie A. Twine Natalie A. Twine Denis C. Bauer Denis C. Bauer Denis C. Bauer Dominic B. Rowe Dominic B. Rowe Roger Pamphlett Roger Pamphlett Roger Pamphlett Matthew C. Kiernan Matthew C. Kiernan Vanessa X. Tan Ian P. Blair Gilles J. Guillemin |
author_sort |
Jennifer A. Fifita |
title |
Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis |
title_short |
Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis |
title_full |
Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis |
title_fullStr |
Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis |
title_full_unstemmed |
Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis |
title_sort |
genetic analysis of tryptophan metabolism genes in sporadic amyotrophic lateral sclerosis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-06-01 |
description |
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. |
topic |
sporadic amyotrophic lateral sclerosis (SALS) whole-genome sequence (WGS) tryptophan kynurenine pathway (KP) serotonin |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.701550/full |
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doaj-10afac3979ec4c8fb35c574b87ed23082021-06-14T09:53:35ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-06-011210.3389/fimmu.2021.701550701550Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral SclerosisJennifer A. Fifita0Sandrine Chan Moi Fat1Emily P. McCann2Kelly L. Williams3Natalie A. Twine4Natalie A. Twine5Denis C. Bauer6Denis C. Bauer7Denis C. Bauer8Dominic B. Rowe9Dominic B. Rowe10Roger Pamphlett11Roger Pamphlett12Roger Pamphlett13Matthew C. Kiernan14Matthew C. Kiernan15Vanessa X. Tan16Ian P. Blair17Gilles J. Guillemin18Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaMacquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaMacquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaMacquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaMacquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaAustralian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organization, Health & Biosecurity Flagship, Sydney, NSW, AustraliaAustralian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organization, Health & Biosecurity Flagship, Sydney, NSW, AustraliaDepartment of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaApplied BioSciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, AustraliaMacquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaDepartment of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaDiscipline of Pathology, School of Medical Sciences, University of Sydney, Sydney, NSW, AustraliaDepartment of Neuropathology, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaBrain and Mind Centre, University of Sydney, Sydney, NSW, AustraliaBrain and Mind Centre, University of Sydney, Sydney, NSW, AustraliaInstitute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaMacquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaMacquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaMacquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaThe 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.701550/fullsporadic amyotrophic lateral sclerosis (SALS)whole-genome sequence (WGS)tryptophankynurenine pathway (KP)serotonin |