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Etude des mécanismes physiopathologiques à l’origine des dysfonctionnements du système nerveux central associés aux maladies rares du métabolisme de la vitamine B12 et innovation thérapeutique

Abstract : Genetic defects in vitamin B12 or cobalamin (cbl) metabolism lead to a decrease in methionine synthase activity associated with changes in genes expression such as decreased expression of SIRT1. Patients with inherited defects affecting methionine synthase activity present mainly with hematological but also neurological symptoms that persist despite conventional treatment and correction of biochemical parameters. The overall objective of this project is to develop an innovative therapeutic treatment for the neurocognitive pathologies developed by these patients using two experimental models: a model of transgenic Mtr KO mice in neurons and a cellular model of fibroblasts from patients affected by the cblC and cblG genetic defects.Our results show that the deficiency of methionine synthase activity is associated with mitochondrial dysfunctions in patient cells and cognitive impairment in the Mtr KO mouse model, with high levels of cellular stress in both models. models. Our results after treatment with SRT2104 alone or combined with N-acetylcysteine demonstrate that pharmacological activation of SIRT1 and the use of antioxidants could improve the cognitive deficits in mice and decrease stress levels in patients' cells, suggesting that this treatment could represent an additionaland innovative approach to treat cblC and cblG patients who respond poorly to vitamin B12 treatment.These results could be considered as a proof of concept for possible subsequent clinical studies and thus contribute to the development of an innovative treatment for patients with innate or acquired dysfunction of vitamin B12 metabolism.Keywords:Rare diseases, B12 metabolism, neurological disorders, neurocognitive deficits, therapeutic innovation, SIRT1 activator.
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https://hal.univ-lorraine.fr/tel-03664773
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Submitted on : Wednesday, May 11, 2022 - 11:56:49 AM
Last modification on : Thursday, May 12, 2022 - 11:55:11 AM

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  • HAL Id : tel-03664773, version 1

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Ziad Hassan. Etude des mécanismes physiopathologiques à l’origine des dysfonctionnements du système nerveux central associés aux maladies rares du métabolisme de la vitamine B12 et innovation thérapeutique. Sciences du Vivant [q-bio]. Université de Lorraine, 2021. Français. ⟨NNT : 2021LORR0232⟩. ⟨tel-03664773⟩

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