Modulating BDNF levels improves the phenotype of the Rett syndrome mouse model.

Rett syndrome (RTT) is a severe and intractable neurological disorder caused by mutations of the MECP2 (Methyl CpG binding protein 2) gene, located on the X chromosome.
The MECP2 protein fine-tunes the expression of many genes, including brain-derived neurotrophic factor BDNF. Normalization of BDNF expression only partially rescues the Mecp2 KO mouse phenotype. Huntingtin (HTT), the protein mutated in Huntington’s disease, serves as a scaffold for BDNF-containing vesicles and HTT is also reduced in Mecp2 KO mice.
We used a combination of state-of-the-art microfluidic and videomicroscopy approaches and found that genetic activation of HTT increases BDNF axonal transport in neurons deficient for Mecp2 protein. We demonstrated in vivo that chronic HTT phosphorylation improves phenotype of Mecp2 KO mice. We identified a strategy to activate HTT in Mecp2 KO neurons by inhibiting HTT dephosphorylation. This study identifies HTT and its phosphorylation as a new therapeutic target in RTT and demonstrates that activating endogenous BDNF in the appropriate neuronal circuits is more effective than non specific BDNF overexpression.

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