ghrelin通过lincRNA-p21介导SMD途径调控帕金森病α-突触核蛋白表达的机制研究

Parkinson's disease (PD) is the second most common neurodegenerative disease. The abnormal high expression of α-synuclein (α-Syn) is closely related to the development of PD. Our previous research indicated that the ghrelin was neuroprotective in PD, and it could decrease the level of α-Syn and inhibit the expression of lincRNA-p21. And lincRNA-p21 is reported to be upregulated in the brain tissue of PD patients. And our previous study proved that lincRNA-p21 participated in the neuron loss in PD and it could promote the expression of α-Syn. It could form STAU1 binding site with TGIF1 mRNA and activate Staufen1-meidated mRNA decay (SMD) pathway, and hence weaken the transcription inhibitory effect of TGIF1 on SNCA, which is the encoding gene of α-Syn. Based on these findings, this project aims to reveal the mechanism of lincRNA-p21 regulating α-Syn expression via SMD pathway and clarify the neuroprotective mechanism of ghrelin by regulating lincRNA-p21/TGIF1/SNCA pathway, which could provide new insight into the treatment of PD.

帕金森病（PD）是第二大常见的神经退行性疾病，α-突触核蛋白（α-Syn）表达异常增高与PD的发生发展密切相关。前期研究发现ghrelin在PD中具有神经保护作用，可显著降低α-Syn水平并抑制lincRNA-p21表达。有报道lincRNA-p21在PD患者脑组织中表达显著增高，通过系列前期实验证实lincRNA-p21参与PD神经损伤并调控α-Syn表达，可能通过与转录因子TGIF1 mRNA形成STAU1结合位点、活化Staufen1介导的RNA降解(SMD)途径，进而削弱TGIF1对α-Syn编码基因SNCA的转录抑制作用有关。因此，本课题拟在前期工作基础上，明确lincRNA-p21通过SMD途径影响α-Syn表达的作用机制，阐明ghrelin在PD中通过lincRNA-p21/TGIF1/SNCA途径调控α-Syn表达发挥神经保护作用，以期为PD治疗提供新思路。

帕金森病（Parkinson’s disease, PD）是第二大常见的神经退行性疾病，至今其发病机制尚未完全明确，临床治疗手段受限。ghrelin是一种内源性脑肠肽，近年来研究表明其与帕金森病的发生发展密切相关。本研究基于PD动物及细胞模型，对ghrelin的神经保护作用及机制进行了一系列的探索，重点探究了ghrelin对α-突触核蛋白的调控作用及机制。通过研究发现ghrelin在6-OHDA诱导的PD动物及细胞模型中具有神经保护作用，一方面可以通过活化TFEB介导的自噬途径改善帕金森病自噬流障碍、提高神经细胞整体的蛋白降解能力；另一方面可以通过抑制lincRNA-p21表达、降低Staufen1介导RNA（SMD）途径对TGIF1的降解水平进而抑制α-突触核蛋白表达，从而减轻神经损伤，TGIF1是调控α-突触核蛋白表达的重要因子。然而值得注意的是，在α-突触核蛋白过表达SH-SY5Y细胞模型中，并未观察到与6-OHDA诱导PD模型一致的研究结果，提示基于不同机制的PD模型可能存在多因素共同参与TGIF1对α-突触核蛋白的表达调控作用，这也为本课题组后续研究的开展提供了新思路。综上所述，本项有助于从新的角度探索帕金森病病理生理机制，并为ghrelin作为帕金森病治疗的有效手段提供了新的理论基础。