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应用鞣花酸治疗亨廷顿舞蹈病转基因小鼠的研究
孙勋
Thesis Advisor刘瑞田
2020-09-01
Degree Grantor中国科学院大学
Degree Name硕士
Degree Discipline生物化工
Keyword亨廷顿舞蹈病,鞣花酸,神经炎症,寡聚体,自噬
Abstract

亨廷顿舞蹈病(Huntington's disease,HD)是由含有超长的多聚谷氨酰胺(polyQ)突变的HTT蛋白(mHTT)在神经元内异常聚集引起的神经退行性疾病,临床表现为舞蹈样动作、行动失调和认知功能下降。目前HD的治疗手段仅限于控制症状,尚无有效的治疗药物应用于临床。mHTT易发生构象变化,其错误折叠和异常聚集导致神经炎症,氧化应激,自噬功能障碍和代谢功能紊乱,引起神经元死亡。因此,降低脑内mHTT蛋白水平,增强自噬功能,抑制神经炎症和氧化应激将是治疗HD的重要策略。鞣花酸(Ellagic Acid,EA)是一种来源于石榴等植物的天然多酚化合物,具有抗炎、抗氧化及多种神经保护作用。 近年来的研究表明,EA可影响淀粉样蛋白的聚集、细胞毒性和脑部的炎症反应,对于阿尔茨海默病和帕金森病等神经退行性疾病具有良好的潜在治疗作用,但EA对于HD的治疗作用尚不明确。在本论文工作中,我们通过大肠杆菌系统融合表达获得了mHTT蛋白(HD53Q),并考察了EA对HD53Q的聚集和细胞毒性的影响。结果表明,EA能够显著抑制HD53Q的聚集,明显降低HD53Q 诱导的神经细胞毒性及细胞凋亡。我们进而将EA应用于HD转基因动物模型R6/2小鼠,对 R6/2小鼠连续灌胃给予EA四周后,动物行为学实验结果显示, EA能够明显改善R6/2小鼠的运动协调能力,提高小鼠的记忆力和认知功能。对小鼠脑内病理学的研究表明,EA显著降低了小鼠脑内mHTT及寡聚体水平,减轻了胶质细胞的活化程度及炎症因子的释放,抑制了突触丢失、神经元凋亡及氧化应激水平,增强了自噬功能,这些结果表明, EA是一种较好的具有HD治疗潜力的天然化合物。;Huntington's disease (HD) is a genetic autosomal dominant neurodegenerative disease caused by an extended polyglutamine (polyQ) tract at the N-terminus of huntingtin protein (HTT). The polyQ expansion induces a pathological conformational change in mutant HTT (mHTT), which forms aggregates in both nucleus and cytoplasm of affected neurons. The abnormal aggregation of mHTT plays key a role in the pathogenesis of HD, which leads to neuronal dysfunction and death through multiple mechanisms, including inflammation, oxidative stress, autophagy deficiency and metabolic dysfunction. Strategies to lower mHTT levels, enhance autophagy, inhibit neuroinflammation and oxidative stress may confer therapeutic potential to combat HD. Ellagic acid (EA) is a polyphenolic antioxidant, it can be found in numerous fruits and vegetables such as pomegranates. EA has been marketed as a dietary supplement with various claimed benefits and neuroprotective effects on several neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, while its effect on mHTT pathology is still unknown.In present work, we reported that EA significantly inhibited mHTT aggregation, reduced mHTT-induced neurocytotoxicity and protected against mHTT-induced apoptosis in vitro. When applied EA to R6/2 mouse model of HD, EA significantly attenuated motor and cognitive deficits in R6/2 mice. Moreover, EA markedly lowered mHTT levels, reduced neuroinflammation, rescued synapse loss, decreased oxidative stress and enhanced autophagy in the brains of R6/2 mice. These findings indicated that EA has promising therapeutic potential for HD. 

Language中文
Document Type学位论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/49639
Collection中国科学院过程工程研究所
Recommended Citation
GB/T 7714
孙勋. 应用鞣花酸治疗亨廷顿舞蹈病转基因小鼠的研究[D]. 中国科学院大学,2020.
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