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.

中文翻译：

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亨廷顿蛋白的磷酸化控制BDNF稳态并改善Mecp2基因敲除小鼠的表型。

X连锁的MECP2基因中的突变导致了Rett综合征（RTT），这是一种严重的神经系统疾病，目前尚无治疗方法。几项研究已将MeCP2功能的丧失与脑源性神经营养因子（BDNF）水平的改变联系在一起，但是BDNF的非特异性过表达仅部分改善了Mecp2缺陷型小鼠的表型。我们和其他人以前已经表明，亨廷顿蛋白（HTT）支架分子运动复合物，运输包含BDNF的囊泡，并在Mecp2基因敲除的大脑中表达不足。在这里，我们证明，通过磷酸化模拟突变或磷酸酶钙调神经磷酸酶的抑制来促进Ser421处的HTT磷酸化，可以在皮质口途径中体外恢复内源性BDNF轴突转运，增加纹状体BDNF的利用度和体内的突触连接性，并改善了Mecp2基因敲除小鼠的表型和存活-即使仅在小鼠已经出现症状后才开始治疗。因此，刺激内源性细胞途径可能是治疗RTT患者的一种有前途的方法。