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

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, which suggests we need to identify cellular pathways that selectively enhance BDNF signaling in appropriate neuronal circuits. We and others have previously shown that Huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF-containing vesicles, and is under-expressed in Mecp2 knock-out brains. Here we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho mimetic mutation or inhibition of the phosphatase calcineurin, restored endogenous BDNF axonal transport in vitro, increased striatal BDNF availability and synaptic connectivity in vivo, and improved 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.