Details

Autor(en) / Beteiligte

• Delépine, Chloé
• Meziane, Hamid
• Nectoux, Juliette
• Opitz, Matthieu
• Smith, Amos B
• Ballatore, Carlo
• Saillour, Yoann
• Bennaceur-Griscelli, Annelise
• Chang, Qiang
• Williams, Emily Cunningham
• Dahan, Maxime
• Duboin, Aurélien
• Billuart, Pierre
• Herault, Yann
• Bienvenu, Thierry

Titel

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

Ist Teil von

• Human molecular genetics, 2016-01, Vol.25 (1), p.146-157

Ort / Verlag

England: Oxford University Press (OUP)

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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.