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. T...

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Autores principales:	Patricia Richard, Lucie Kozlowski, Hélène Guillorit, Patrice Garnier, Nicole C McKnight, Antoine Danchin, Xavier Manière
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d55364b9d2f442329792ee80c6803aa1
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spelling	oai:doaj.org-article:d55364b9d2f442329792ee80c6803aa12021-12-02T20:18:26ZQueuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration.1932-620310.1371/journal.pone.0253216https://doaj.org/article/d55364b9d2f442329792ee80c6803aa12021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253216https://doaj.org/toc/1932-6203Growing 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.Patricia RichardLucie KozlowskiHélène GuilloritPatrice GarnierNicole C McKnightAntoine DanchinXavier ManièrePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0253216 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Patricia Richard Lucie Kozlowski Hélène Guillorit Patrice Garnier Nicole C McKnight Antoine Danchin Xavier Manière Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration.
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	article
author	Patricia Richard Lucie Kozlowski Hélène Guillorit Patrice Garnier Nicole C McKnight Antoine Danchin Xavier Manière
author_facet	Patricia Richard Lucie Kozlowski Hélène Guillorit Patrice Garnier Nicole C McKnight Antoine Danchin Xavier Manière
author_sort	Patricia Richard
title	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_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_sort	queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/d55364b9d2f442329792ee80c6803aa1
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Queuine, a bacterial-derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration.

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