Brain-specific NRSF deficiency aggravates dopaminergic neurodegeneration ana impairs neurogenesis in the MPTP mouse model of Parkinson's disease
Brain-specific NRSF deficiency aggravates dopaminergic neurodegeneration ana impairs neurogenesis in the MPTP mouse model of Parkinson's disease
复制标题
大脑特异性 NRSF 缺乏会加重多巴胺能神经变性，并损害帕金森病 MPTP 小鼠模型的神经发生
DOI：
10.18632/aging.101979
复制
发表时间：
2019-05-31
期刊：
影响因子：
5.2
通讯作者：
Huang, Fang
中科院分区：
文献类型：
--
作者：
Huang, Dongping;Li, Qing;Huang, Fang
黑质中多巴胺能神经元的变性以及由此导致的纹状体多巴胺耗竭是帕金森病（PD）的标志性特征，并是该疾病主要运动症状的原因。转录抑制因子神经元限制性沉默因子（NRSF），也称为RE1沉默转录因子（REST），最初被鉴定为非神经元细胞中神经元特异性基因的负调控因子。我们之前的研究表明，神经元NRSF/REST表达缺失的小鼠更容易受到多巴胺能神经毒素1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶（MPTP）的有害影响。在此，我们发现NRSF/REST在大脑中的特异性缺失导致黑质 - 纹状体通路受到更严重的损伤，并且在MPTP处理的小鼠中出现长期的行为障碍。此外，与野生型对照相比，这些小鼠在MPTP暴露后不久神经发生增加，但随后神经发生减少。这些结果表明，在正常条件下以及帕金森病进程中，NRSF/REST作为神经发生的负调控因子以及神经干细胞的促存活因子发挥作用。
Degeneration of the dopaminergic neurons in the substantia nigra and the resultant dopamine depletion from the striatum are the hallmarks of Parkinson's disease (PD) and are responsible for the disease's cardinal motor symptoms. The transcriptional repressor Neuron-Restrictive Silencer Factor (NRSF), also known as RE1-Silencing Transcription Factor (REST), was originally identified as a negative regulator of neuron-specific genes in non-neuronal cells. Our previous study showed that mice deficient in neuronal NRSF/REST expression were more vulnerable to the noxious effects of the dopaminergic neurotoxin MPTP. Here, we found that brain-specific deletion of NRSF/REST led to more severe damages to the nigrostriatal pathway and long-lasting behavioral impairments in mice challenged with MPTP. Moreover, compared to wild-type controls, these mice showed increased neurogenesis shortly after MPTP exposure, but reduced neurogenesis later on. These results suggest that NRSF/REST acts as a negative modulator of neurogenesis and a pro-survival factor of neural stem cells under both normal conditions and during the course of PD.