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Hum Mol Genet. 2016 Jan 1;25(1):146-57. doi: 10.1093/hmg/ddv464. Epub 2015 Nov 24.

Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes.

Author information

1
Inserm, U1016, Institut Cochin, Paris, France, Cnrs, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
2
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.
3
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.
4
Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
5
Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA, Center of Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.
6
ESTeam Paris-Sud, Université Paris-Sud 11, Inserm U935, Villejuif, France.
7
Department of Genetics and Neurology, University of Wisconsin-Madison, Madison, WI, USA.
8
Laboratoire Physico-Chimie Curie, Institut Curie, CNRS UMR168, UPMC, Paris, France and.
9
Laboratoire Physico-Chimie Curie, Institut Curie, CNRS UMR168, UPMC, Paris, France and ALVEOLE, Paris, France.
10
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.

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.

PMID:
26604147
PMCID:
PMC4690499
DOI:
10.1093/hmg/ddv464
[Indexed for MEDLINE]
Free PMC Article

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