表观遗传修饰对pro-BDNF/BDNF平衡的调控对帕金森病发病的影响

Parkinson’s disease (PD) is the second most common neurodegenerative disease, which causes global health burden in elders. The loss of dopaminergic neurons in substantianigra is a major risk factor for PD development. It has been reported that dopaminergic neuronscan be protected by BDNF (brain-derived neurotrophic factor) , whereas pro-BDNF negatively regulates the survival of neurons and the function of axons. Thus, we proposed that the imbalance between pro-BDNF and BDNF expression may lead to the development of PD. We have previously found that the transcript levels of BDNF II、 III、IV、V and VII in substantianigra of MPTP-induced PD mouse are increased compared with the controls. In addition, HDAC inhibitors could upregulate the expression of BDNF in substantianigra and restore the level of dopaminergic neurons in striatum, suggesting that histone acetylation and methylation at BDNF promoter may be involved in regulating the expression of different BDNF transcripts in substantianigra. However, the dynamic relationship between the expression of different BDNF transcripts and Pro-BDNF remains unclear.In this project, we will focus on revealing the role of H3K4me3, H3K4me3 and H3K9me3 epigenetic modifications on regulating different BDNF transcripts expression in substantianigra of PD mouse model and pro-BDNF-induced degeneration and apoptosis of dopaminergic neurons. This project will pave the road for precision medicine in PD treatment by targeting specific BDNF transcripts.

PD是全球第二大神经系统退行性疾病，黑质DA能神经元减少是PD发生的直接原因。BDNF对黑质DA能神经元有保护作用。BDNF首先以pro-BDNF形式在细胞中合成，Pro-BDNF与BDNF平衡失调导致疾病发生进展，Pro-BDNF的表达受表观遗传学调控。我们前期研究发现，LPS可降低PD大鼠黑质BDNF表达，此作用可被HDACi逆转；QRT-PCR检测提示：正常小鼠黑质II、 III、IV、V、VII转录本表达显著高于其他转录本；模型组小鼠黑质上述转录本表达高于正常小鼠。本研究拟在前期研究基础上，明确pro-BDNF／p75NTR与mature-BDNF／trkB的变化，在细胞及小鼠模型中探讨BDNF基因转录本与pro-BDNF表达间的关系，进一步探讨组蛋白乙酰化及甲基化是否通过调控pro-BDNF发挥对DA能神经元的保护，为后续以特异性BDNF转录本为靶标的精准治疗临床研究提供实验依据

帕金森病（Parkinson's disease，PD）是全球第二大神经系统退行性疾病，目前具体发病原因及机制未完全阐明，也无具体根治治疗方法。黑质多巴胺能神经元减少是PD发生的直接原因，神经炎症是其发病机制之一。脑源性神经营养因子（Brain-derived neurotrophic factor，BDNF）.对黑质多巴胺能神经元有保护作用，研究表明BDNF首先以pro-BDNF形式在细胞中合成，Pro-BDNF与BDNF平衡失调导致疾病发生进展，Pro-BDNF的表达受表观遗传学调控。另相关研究证实由活化的神经胶质细胞介导神经炎症在帕金森病的发生发展中起重要作用，ATP敏感性钾通道(ATP-sensitive potassium channels,KATP)是内向整流钾通道的成员，调控KATP通道会影响PD中小胶质细胞的活化和黑质多巴胺能神经元的活性。丁酸钠（Sodium butyrate,NaB）是种重要神经保护剂，也是一种重要的乙酰化酶抑制剂，研究显示NaB可刺激组蛋白乙酰化表达，上调BDNF。除此之外，NaB可通过下调促炎介质和上调抗炎介质的表达来调节小胶质细胞的炎症反应，从而发挥其神经保护作用。本研究通过Western blot,免疫荧光，免疫组化，qPCR，动物行为学等实验，从细胞及动物实验层面证实了NaB可通过调控ProBDNF/BDNF表达比例，增强BDNF在机体表达以及调控KATP通道抑制小胶质细胞的活化和炎症反应，从而对PD起保护作用。相关实验结果丰富PD发病机制研究，为今后PD治疗提供策略。