Fiche publication
Date publication
janvier 2016
Journal
Human molecular genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Dr HERAULT Yann
Tous les auteurs :
Delépine C, Meziane H, Nectoux J, Opitz M, Smith AB, Ballatore C, Saillour Y, Bennaceur-Griscelli A, Chang Q, Williams EC, Dahan M, Duboin A, Billuart P, Herault Y, Bienvenu T
Lien Pubmed
Résumé
Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder, characterized by normal post-natal development followed by a sudden deceleration in brain growth with progressive loss of acquired motor and language skills, stereotypic hand movements and severe cognitive impairment. Mutations in the methyl-CpG-binding protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, and that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern and greatly prolonged lifespan compared with globally null mice. We now report that microtubule (MT)-dependent vesicle transport is altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared with control wild-type littermates. Similar observation has been made in human MECP2 p.Arg294* iPSC-derived astrocytes. Importantly, administration of Epothilone D, a brain-penetrant MT-stabilizing natural product, was found to restore MT dynamics in Mecp2-deficient astrocytes and in MECP2 p.Arg294* iPSC-derived astrocytes in vitro. Finally, we report that relatively low weekly doses of Epothilone D also partially reversed the impaired exploratory behavior in Mecp2(308/y) male mice. These findings represent a first step toward the validation of an innovative treatment for RTT.
Mots clés
Acetylation, Animals, Arginine, metabolism, Astrocytes, drug effects, Cell Line, Cells, Cultured, Epothilones, pharmacology, Histone Deacetylases, metabolism, Humans, Male, Methyl-CpG-Binding Protein 2, metabolism, Mice, Mice, Inbred C57BL, Microtubules, drug effects, Pluripotent Stem Cells, metabolism, Rett Syndrome, metabolism, Transport Vesicles, metabolism, Tubulin, metabolism, Tubulin Modulators, pharmacology
Référence
Hum. Mol. Genet.. 2016 Jan;25(1):146-57
