title: Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes.
abstract: 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.
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France, Cnrs, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Delépine
authors.affiliation: Institut Clinique de la Souris (ICS), PHENOMIN, GIE CERBM, Illkirch, France, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France, Centre National de la Recherche Scientifique, UMR7104, Illkirch, France, Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France, Université de Strasbourg, Illkirch, France.
authors.forename: Hamid
authors.initials: H
authors.lastname: Meziane
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France, Cnrs, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Laboratoire de Biologie et Génétique Moléculaires, HUPC, Hôpital Cochin, Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Nectoux
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France, Cnrs, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Opitz
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA, Center of Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France, Cnrs, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Saillour
authors.affiliation: ESTeam Paris-Sud, Université Paris-Sud 11, Inserm U935, Villejuif, France.
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.affiliation: Department of Genetics and Neurology, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Genetics and Neurology, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Emily Cunningham
authors.initials: EC
authors.lastname: Williams
authors.affiliation: Laboratoire Physico-Chimie Curie, Institut Curie, CNRS UMR168, UPMC, Paris, France and.
authors.forename: Maxime
authors.initials: M
authors.lastname: Dahan
authors.affiliation: Laboratoire Physico-Chimie Curie, Institut Curie, CNRS UMR168, UPMC, Paris, France and ALVEOLE, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Duboin
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France, Cnrs, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
authors.affiliation: Institut Clinique de la Souris (ICS), PHENOMIN, GIE CERBM, Illkirch, France, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France, Centre National de la Recherche Scientifique, UMR7104, Illkirch, France, Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France, Université de Strasbourg, Illkirch, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France, Cnrs, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Laboratoire de Biologie et Génétique Moléculaires, HUPC, Hôpital Cochin, Paris, France, thierry.bienvenu@inserm.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
mesh_terms: D000107:Acetylation; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D034261:Epothilones / Q000494:pharmacology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000378:metabolism; D015518:Rett Syndrome / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D034261:Epothilones; D051783:Methyl-CpG-Binding Protein 2; D014404:Tubulin; D050257:Tubulin Modulators; D001120:Arginine; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases