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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.

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