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

作者：Delepine Chloe; Meziane Hamid; Nectoux Juliette; Opitz Matthieu; Smith Amos B; Ballatore Carlo; Saillour Yoann; Bennaceur Griscelli Annelise; Chang Qiang; Williams Emily Cunningham; Dahan Maxime; Duboin Aurelien; Billuart Pierre; Herault Yann; Bienvenu Thierry^*

来源：Human Molecular Genetics, 2016, 25(1): 146-157.

DOI：10.1093/hmg/ddv464

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 Dalso partially reversed the impaired exploratory behavior in Mecp(2308/y) male mice. These findings represent a first step toward the validation of an innovative treatment for RTT.

• 出版日期2016-1-1