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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236844/ https://www.ncbi.nlm.nih.gov/pubmed/34194442 http://dx.doi.org/10.3389/fimmu.2021.701550 |
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author | Fifita, Jennifer A. Chan Moi Fat, Sandrine McCann, Emily P. Williams, Kelly L. Twine, Natalie A. Bauer, Denis C. Rowe, Dominic B. Pamphlett, Roger Kiernan, Matthew C. Tan, Vanessa X. Blair, Ian P. Guillemin, Gilles J. |
author_facet | Fifita, Jennifer A. Chan Moi Fat, Sandrine McCann, Emily P. Williams, Kelly L. Twine, Natalie A. Bauer, Denis C. Rowe, Dominic B. Pamphlett, Roger Kiernan, Matthew C. Tan, Vanessa X. Blair, Ian P. Guillemin, Gilles J. |
author_sort | Fifita, Jennifer A. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-8236844 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82368442021-06-29 Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis Fifita, Jennifer A. Chan Moi Fat, Sandrine McCann, Emily P. Williams, Kelly L. Twine, Natalie A. Bauer, Denis C. Rowe, Dominic B. Pamphlett, Roger Kiernan, Matthew C. Tan, Vanessa X. Blair, Ian P. Guillemin, Gilles J. Front Immunol Immunology 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. Frontiers Media S.A. 2021-06-14 /pmc/articles/PMC8236844/ /pubmed/34194442 http://dx.doi.org/10.3389/fimmu.2021.701550 Text en Copyright © 2021 Fifita, Chan Moi Fat, McCann, Williams, Twine, Bauer, Rowe, Pamphlett, Kiernan, Tan, Blair and Guillemin https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Fifita, Jennifer A. Chan Moi Fat, Sandrine McCann, Emily P. Williams, Kelly L. Twine, Natalie A. Bauer, Denis C. Rowe, Dominic B. Pamphlett, Roger Kiernan, Matthew C. Tan, Vanessa X. Blair, Ian P. Guillemin, Gilles J. Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis |
title | 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_short | Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis |
title_sort | genetic analysis of tryptophan metabolism genes in sporadic amyotrophic lateral sclerosis |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236844/ https://www.ncbi.nlm.nih.gov/pubmed/34194442 http://dx.doi.org/10.3389/fimmu.2021.701550 |
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