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.

译文

:X连锁的MECP2基因突变导致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)水平的改变联系起来,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(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,我们证明通过模仿磷酸酯酶的磷酸化突变或抑制磷酸钙调神经磷酸酶来促进Ser421处的HTT磷酸化,可在皮质口途径中体外恢复内源性BDNF轴突运输,增加纹状体BDNF的可用性和体内突触连接性,并改善表型和Mecp2基因敲除小鼠的存活-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。

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