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Rett Syndrome: Huntingtin to the rescue

on the January 13, 2020
Mutations in the X-linked MECP2 (Methyl-CpG-binding protein2) gene are responsible for Rett syndrome, a severe neurological disorder. MECP2 encodes MeCP2 protein, a transcriptional regulator. Several studies have functionally linked the loss of MeCP2 function to alterations of BDNF (brain-derived neurotrophic factor) levels in the brain of RTT patients as well as in mouse models. Transport of BDNF-containing vesicles from the cortex to the striatum is abnormally reduced in Mecp2 knockout (KO) mouse neurons and involves HTT (Huntingtin). In the present study we tested the possibility that promoting HTT function in transport via its phosphorylation at Serine 421 (S421) could be of therapeutic interest in Mecp2 KO cells.
We used genetic -phospho-mimetic mutation- and pharmacological –inhibition of the phosphatase calcineurin- approaches to promote HTT phosphorylation of S421 in Mecp2-deficient neurons and Mecp2 KO mice. We evaluated the consequences of HTT S421 phosphorylation on BDNF axonal trafficking in projecting corticostriatal neurons using microfluidic devices that mimic the excitatory network and, in vivo, assessing the behavior of Mecp2 KO mice. Our results demonstrate that specific targeting of huntingtin phosphorylation restores the intracellular trafficking of BDNF in Mecp2-silenced neurons, improves drastically several key symptoms and increases longevity in a mouse model of Rett syndrome.
Our study identifies HTT and its phosphorylation as a new therapeutic target in RTT. It also demonstrates that promoting BDNF transport in the appropriate neuronal circuits is more effective at restoring normal function in neurons depleted of MecP2 than non-specific BDNF overexpression. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients.


Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice. Ehinger Y, Bruyère J, Panayotis N, Abada YS, Borloz E, Matagne V, Scaramuzzino C, Vitet H, Delatour B, Saidi L, Villard L, Saudou F, Roux JC. EMBO Mol Med. 2020 Jan 8:e10889. doi: 10.15252/emmm.201910889. *co-corresponding authors.

Updated on January 14, 2020

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