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

Mutations in the X-linked 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 -deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF-containing vesicles, and is under-expressed in knock-out 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 the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity , and improves the phenotype and the survival of 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.