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Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration
Growing evidence suggests that human gut bacteria, which comprise the microbiome, are linked to several neurodegenerative disorders. An imbalance in the bacterial population in the gut of Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients has been detected in several studies. This dysbio...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357117/ https://www.ncbi.nlm.nih.gov/pubmed/34379627 http://dx.doi.org/10.1371/journal.pone.0253216 |
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author | Richard, Patricia Kozlowski, Lucie Guillorit, Hélène Garnier, Patrice McKnight, Nicole C. Danchin, Antoine Manière, Xavier |
author_facet | Richard, Patricia Kozlowski, Lucie Guillorit, Hélène Garnier, Patrice McKnight, Nicole C. Danchin, Antoine Manière, Xavier |
author_sort | Richard, Patricia |
collection | PubMed |
description | Growing evidence suggests that human gut bacteria, which comprise the microbiome, are linked to several neurodegenerative disorders. An imbalance in the bacterial population in the gut of Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients has been detected in several studies. This dysbiosis very likely decreases or increases microbiome-derived molecules that are protective or detrimental, respectively, to the human body and those changes are communicated to the brain through the so-called ‘gut-brain-axis’. The microbiome-derived molecule queuine is a hypermodified nucleobase enriched in the brain and is exclusively produced by bacteria and salvaged by humans through their gut epithelium. Queuine replaces guanine at the wobble position (position 34) of tRNAs with GUN anticodons and promotes efficient cytoplasmic and mitochondrial mRNA translation. Queuine depletion leads to protein misfolding and activation of the endoplasmic reticulum stress and unfolded protein response pathways in mice and human cells. Protein aggregation and mitochondrial impairment are often associated with neural dysfunction and neurodegeneration. To elucidate whether queuine could facilitate protein folding and prevent aggregation and mitochondrial defects that lead to proteinopathy, we tested the effect of chemically synthesized queuine, STL-101, in several in vitro models of neurodegeneration. After neurons were pretreated with STL-101 we observed a significant decrease in hyperphosphorylated alpha-synuclein, a marker of alpha-synuclein aggregation in a PD model of synucleinopathy, as well as a decrease in tau hyperphosphorylation in an acute and a chronic model of AD. Additionally, an associated increase in neuronal survival was found in cells pretreated with STL-101 in both AD models as well as in a neurotoxic model of PD. Measurement of queuine in the plasma of 180 neurologically healthy individuals suggests that healthy humans maintain protective levels of queuine. Our work has identified a new role for queuine in neuroprotection uncovering a therapeutic potential for STL-101 in neurological disorders. |
format | Online Article Text |
id | pubmed-8357117 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-83571172021-08-12 Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration Richard, Patricia Kozlowski, Lucie Guillorit, Hélène Garnier, Patrice McKnight, Nicole C. Danchin, Antoine Manière, Xavier PLoS One Research Article Growing evidence suggests that human gut bacteria, which comprise the microbiome, are linked to several neurodegenerative disorders. An imbalance in the bacterial population in the gut of Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients has been detected in several studies. This dysbiosis very likely decreases or increases microbiome-derived molecules that are protective or detrimental, respectively, to the human body and those changes are communicated to the brain through the so-called ‘gut-brain-axis’. The microbiome-derived molecule queuine is a hypermodified nucleobase enriched in the brain and is exclusively produced by bacteria and salvaged by humans through their gut epithelium. Queuine replaces guanine at the wobble position (position 34) of tRNAs with GUN anticodons and promotes efficient cytoplasmic and mitochondrial mRNA translation. Queuine depletion leads to protein misfolding and activation of the endoplasmic reticulum stress and unfolded protein response pathways in mice and human cells. Protein aggregation and mitochondrial impairment are often associated with neural dysfunction and neurodegeneration. To elucidate whether queuine could facilitate protein folding and prevent aggregation and mitochondrial defects that lead to proteinopathy, we tested the effect of chemically synthesized queuine, STL-101, in several in vitro models of neurodegeneration. After neurons were pretreated with STL-101 we observed a significant decrease in hyperphosphorylated alpha-synuclein, a marker of alpha-synuclein aggregation in a PD model of synucleinopathy, as well as a decrease in tau hyperphosphorylation in an acute and a chronic model of AD. Additionally, an associated increase in neuronal survival was found in cells pretreated with STL-101 in both AD models as well as in a neurotoxic model of PD. Measurement of queuine in the plasma of 180 neurologically healthy individuals suggests that healthy humans maintain protective levels of queuine. Our work has identified a new role for queuine in neuroprotection uncovering a therapeutic potential for STL-101 in neurological disorders. Public Library of Science 2021-08-11 /pmc/articles/PMC8357117/ /pubmed/34379627 http://dx.doi.org/10.1371/journal.pone.0253216 Text en © 2021 Richard et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Richard, Patricia Kozlowski, Lucie Guillorit, Hélène Garnier, Patrice McKnight, Nicole C. Danchin, Antoine Manière, Xavier Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration |
title | Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration |
title_full | Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration |
title_fullStr | Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration |
title_full_unstemmed | Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration |
title_short | Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration |
title_sort | queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357117/ https://www.ncbi.nlm.nih.gov/pubmed/34379627 http://dx.doi.org/10.1371/journal.pone.0253216 |
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