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Modulation des mécanismes de Contrôle Qualité des Protéines dans la dystrophie musculaire de Duchenne

Abstract : Various studies have highlighted the importance of Protein Quality Control (PQC), including protein refolding (molecular chaperones) and degradation (autophagy, proteasome) mechanisms in inherited muscle disorders such as Ullrich Congenital Muscular Dystrophy (UCMD), Duchenne Muscular Dystrophy (DMD) or Emery-Dreifuss Muscular Dystrophy (EDMD); however, to date, no extensive study has been conducted on these mechanisms in a same model, in muscle cells before muscle differentiation. Thus, we were interested in PQC mechanisms functionality and their interconnection in human immortalized myoblasts from healthy donors or patients suffering from DMD. We observed an increase of protein aggregation in DMD cells. This phenomenon is accompanied by a deregulation of sequestration mechanisms by molecular chaperones, reflected by the modulation of HSPB5 and HSPB8 expression. Degradation mechanisms are also deregulated; indeed, we observed on one hand a decrease of proteasome enzymatic activity and multiubiquitinated proteins UPS-adressing molecules and on the other hand, an increase of NF?B transcription factor’s activity, involved in autophagy, and of BAG3/HSPB8 complexes, leading to an increase of the autophagic flux. These PQC defects reflect the existence of a protein aggregation stress in myoblasts coming from DMD patients. In this context, pharmacological modulation of PQC in these cells could represent a new therapeutic strategy for Duchenne Muscular Dystrophy
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Submitted on : Thursday, April 19, 2018 - 4:00:06 PM
Last modification on : Thursday, February 6, 2020 - 10:56:02 AM
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  • HAL Id : tel-01771583, version 1

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Marion Wattin. Modulation des mécanismes de Contrôle Qualité des Protéines dans la dystrophie musculaire de Duchenne. Biologie moléculaire. Université de Lyon, 2017. Français. ⟨NNT : 2017LYSE1323⟩. ⟨tel-01771583⟩

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