Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice.

Frédéric Saudou,Yann Ehinger,Nicolas Panayotis,Benoit Delatour,Emilie Borloz,Lydia Saidi,Hélène Vitet,Laurent Villard,Julie Bruyère,Yah‐Se Abada,Valérie Matagne,Chiara Scaramuzzino,Jean‐Christophe Roux

doi:10.15252/emmm.201910889

Abstract

Mutations in the X‐linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder for which there is no treatment. Several studies have linked the loss of MeCP2 function to alterations of brain‐derived neurotrophic factor (BDNF) levels, but non‐specific overexpression of BDNF only partially improves the phenotype of Mecp2‐deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF‐containing vesicles, and is under‐expressed in Mecp2 knockout brains. Here, we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho‐mimetic mutation or inhibition of the phosphatase calcineurin, restores endogenous BDNF axonal transport in vitro in the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of Mecp2 knockout mice—even though treatments were initiated only after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients.

Highlights

MeCP2 (Methyl-CpG-binding protein 2) is one of the most abundant proteins in the brain, yet the precise nature of its activities remains controversial
We focused here on the corticostriatal network, which is altered in Rett syndrome (RTT) and Mecp2 knockout mice (KO) mice (Roux et al, 2012; Xu et al, 2014)
The overall effect of HTT phosphorylation on brain-derived neurotrophic factor (BDNF) transport under normal or low-Mecp2 conditions was not due to a change in the number of moving BDNF vesicles (Fig EV1D and F) or in cell viability, since we observed no toxicity in Mecp2 siRNA-transfected HTTSD or HTTSA neurons compared to Mecp2 siRNA-transfected WT neurons (Fig 1F). These results demonstrate that genetically promoting HTT phosphorylation at serine 421 (S421) rescues the transport of BDNF vesicles in projecting corticostriatal siMecp2 neurons

Summary

Introduction

MeCP2 (Methyl-CpG-binding protein 2) is one of the most abundant proteins in the brain, yet the precise nature of its activities remains controversial It was originally discovered as a DNA methylationdependent transcriptional repressor (Meehan et al, 1992), but has been shown to play various roles in chromatin compaction, global gene expression, alternative splicing, and miRNA processing (Young et al, 2005; Chahrour et al, 2008; Skene et al, 2010; Cheng et al, 2014). Interest in this protein rose sharply after it was discovered that mutations in MECP2 cause Rett syndrome (RTT), a severe developmental disorder (Amir et al, 1999; Lyst & Bird, 2015).

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