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Queuine, a bacterial derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration

View ORCID ProfilePatricia Richard, Xavier Manière, Lucie Kozlowski, Hélène Guillorit, Patrice Garnier, Antoine Danchin, Nicole C. McKnight
doi: https://doi.org/10.1101/2021.01.20.427538
Patricia Richard
1Stellate Therapeutics Inc., 101 Avenue of the Americas, JLABS @ NYC, New York, NY 10013
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  • ORCID record for Patricia Richard
Xavier Manière
2Stellate Therapeutics SAS, 47 rue de Montmorency, 75003, Paris, France
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Lucie Kozlowski
2Stellate Therapeutics SAS, 47 rue de Montmorency, 75003, Paris, France
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Hélène Guillorit
2Stellate Therapeutics SAS, 47 rue de Montmorency, 75003, Paris, France
3Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094, Montpellier, France
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Patrice Garnier
2Stellate Therapeutics SAS, 47 rue de Montmorency, 75003, Paris, France
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Antoine Danchin
4Kodikos Labs, Institut Cochin, 24 rue du Faubourg Saint-Jacques, 75014, Paris, France
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Nicole C. McKnight
1Stellate Therapeutics Inc., 101 Avenue of the Americas, JLABS @ NYC, New York, NY 10013
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  • For correspondence: ncm@stellate-tx.com
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Abstract

Growing evidence suggests that human gut bacteria, comprising the microbiome that communicates with the brain through the so-called ‘gut-brain-axis’, are linked to neurodegenerative disorders. Imbalances in the microbiome of Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients have been detected in several studies. Queuine is a hypermodified nucleobase enriched in the brain and exclusively produced by bacteria and salvaged by humans through their gut epithelium. Queuine replaces guanine at the wobble position of tRNAs with GUN anticodons and promotes efficient cytoplasmic and mitochondrial mRNA translation.

To elucidate whether queuine could facilitate protein folding and prevent aggregation and mitochondrial defects, hallmarks of neurodegenerative disorders, we tested the effect of chemically synthesized queuine, STL-101, in several in vitro models of neurodegeneration. Treatment with STL-101 led to increased neuronal survival as well as a significant decrease in hyper-phosphorylated alpha-synuclein, a marker of alpha-synuclein aggregation in a PD model and a decrease in tau hyperphosphorylation in an AD model. Our work has identified a new role for queuine in neuroprotection uncovering a therapeutic potential for STL-101 in neurological disorders.

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Posted January 22, 2021.
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Queuine, a bacterial derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration
Patricia Richard, Xavier Manière, Lucie Kozlowski, Hélène Guillorit, Patrice Garnier, Antoine Danchin, Nicole C. McKnight
bioRxiv 2021.01.20.427538; doi: https://doi.org/10.1101/2021.01.20.427538
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Queuine, a bacterial derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration
Patricia Richard, Xavier Manière, Lucie Kozlowski, Hélène Guillorit, Patrice Garnier, Antoine Danchin, Nicole C. McKnight
bioRxiv 2021.01.20.427538; doi: https://doi.org/10.1101/2021.01.20.427538

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