帕金森病（Parkinson's disease,PD）是中枢神经系统第二大退行性病，以中脑黑质多巴胺能神经元进行性丢失为特征，目前仍没有很有效的治疗手段。随着PD病理研究的深入，人们发现表观遗传机制在PD的发生发展中具有重要的作用。神经元限制性沉默因子（NRSF/REST）是一种具有锌指结构的、转录沉默的主控因子，可以关闭神经元特异性基因在非神经细胞中的表达，控制神经元的形成与分化。我们建立了NRSF/REST神经元条件性剔除（cKO）小鼠，发现cKO小鼠对神经毒素MPTP更加敏感，组蛋白去乙酰化酶抑制剂TSA在野生型小鼠中具有明显的保护作用，体现在:1）减少了多巴胺能神经元的丢失；2）提高了纹状体多巴胺递质的含量；3）改善了小鼠的运动平衡能力，而TSA的作用在cKO小鼠中消失。本申请将深入研究NRSF/REST在TSA多巴胺能神经保护作用中的机制，为表观遗传治疗PD提供理论与实验依据。

Parkinson's disease (PD) is the second most common neurodegenerative disease in the central nervous system, charaterized by the progresive loss of midbrain dopaminergic neurons. At present, the therapeutic strategy is quite limited. More evidences prove that epigentic mechanisms play an important role in the development of PD. Neuron-restrictive silencer factor/Repressor element 1 silencing transcription factor (NRSF/REST),belonging to the zinc-finger family of transcription factors, is a master transcription silencing factor.NRSF/REST blocks the expression of many neuronal genes in non-neuronal and neural stem cells, thus controls neurogenesis and neuronal differentiation. Previously, we found NRSF/REST neuronal deficient mice (cKO) were more vulnerable to the neurotoxin MPTP. Histone deacetylase (HDAC) inhibitor TSA significantly protected wild type mice from MPTP injury through 1) reducing the loss of dopaminergic neurons; 2) improving the striatal dopamine concentraiton;3) ameliorating the behavior deficiency in rotarod test. However, the neuroprotection of TSA in MPTP-PD model was disappeared in cKO mice. In the present research, we will further decipher the mechanisms involved in NRSF/REST mediated neuroprotection of HDAC inhibitor TSA in PD, and provide theoretic and experimental rationales for the potential epigenetic therapy of PD.