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Les agrégats de PABPN1 dans la dystrophie musculaire oculopharyngée

Abstract : Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal genetic disease characterized by a restrictive muscle weakness: pharyngeal muscles (including cricopharyngeal muscle (CPM)) as well as eyelid muscles are primarly affected leading to swallowing difficulties (dysphagia) and eyelid drooping (ptosis) respectively. This disease stems from a short polyalanine expansion in the Poly(A) Binding Protein Nuclear 1 (PABPN1) leading to the formation of nuclear aggregates in the muscle of OPMD patients. The objectives of this study are : 1/ to characterize PABPN1 nuclear aggregates on human muscle biopsies to evaluate if age and genotype influence their features and 2/ to assess the efficacy of the anti-aggregates molecule guanabenz (GA) on mammalian models of OPMD. The results show that aging and genotype of OPMD patients influence the size, the percentage or the composition of nuclear aggregates. Treatment of cellular and mouse model of OPMD with guanabenz allows a diminution in the percentage and the size of nuclear aggregates as well as an improvement of the mice muscle phenotype. GA acts through the unfolded protein response to endoplasmic reticulum stress (ER) showing for the first time that ER stress is activated in OPMD. This study suggestes that the use of pharmacological molecules modulating notably ER stress is a promising strategy to treat OPMD.
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Submitted on : Monday, March 8, 2021 - 2:55:15 PM
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  • HAL Id : tel-03162426, version 1

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Fanny Roth. Les agrégats de PABPN1 dans la dystrophie musculaire oculopharyngée. Biologie moléculaire. Sorbonne Université, 2019. Français. ⟨NNT : 2019SORUS342⟩. ⟨tel-03162426⟩

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