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Etude des mécanismes impliqués dans la mort oligodendrocytaire induite par la protéolipide-protéine mutée : rôle du stress du réticulum endoplasmique et identification des modulateurs à fort potentiel pour le traitement des pathologies dysmyélinisantes

Abstract : Mutations of proteolipid-protein (PLP) cause oligodendrocyte (OL) death and myelin disorders. To contribute to the elucidation of the mechanisms involved, the present PhD work has used 158N (normal) and 158JP (mutated PLP) OL lines, to show the occurrence of a high cell death percentage in 158JP OL cultures compared to the controls. An increased Bax (pro-)/Bcl2 (anti-apoptosis) ratio is evidenced in 158JP cells. Also, the endoplasmic reticulum stress marker (SRE) BiP is overexpressed in 158JP OL. Exposure of 158N and 158JP cells to tunicamycin-induced SRE revealed that the ED50 for 158JP OL is 67 times lower than the ED50 for 158N OL. Proteins CHOP and caspase-12, that pivotally determine the switching from survival to apoptotic pathways, are upregulated in 158JP cells. 4-Phenylbutyrate, a SRE inhibitor, which improves 158JP cell survival, also decreases the levels of SRE and apoptosis markers in 158JP OL. The thesis opens promising perspectives for the development of effective strategies against myelin disorders.
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https://tel.archives-ouvertes.fr/tel-01707470
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Submitted on : Monday, February 12, 2018 - 6:16:08 PM
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Anne-Sophie Wilding. Etude des mécanismes impliqués dans la mort oligodendrocytaire induite par la protéolipide-protéine mutée : rôle du stress du réticulum endoplasmique et identification des modulateurs à fort potentiel pour le traitement des pathologies dysmyélinisantes. Neurosciences. Université de Strasbourg, 2017. Français. ⟨NNT : 2017STRAJ073⟩. ⟨tel-01707470⟩

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