miRNA调控自噬在PIMT缺失引起神经退行性病变中的作用及羟基积雪草苷干预研究

Formation of Isoaspartate(IsoAsp) in proteins during brain aging, which could contribute to metabolic dysfunctions in neuronal cells reducing cognitive functions in elderly patients and would eventually promote the development of neurodegenerative diseases. IsoAsp can be recognized and repaired by protein L-isoaspartyl methyltransferase (PIMT). PIMT dysfunction has been reported to be involved in brain damage of patients with neurodegenerative diseases, but the molecular mechanism has not been fully clarified. In our primary study, cell degeneration of hippocampus dentate gyrus cell, post-translational modification of synaptic protein synapsin, oxidative stress, autophagy and microRNA(miRNA) dysregulation were observed in PIMT knockout mouse brain. These neurodegenerative pathological changes could be improved by Madecassoside(MC), a triterpenoid saponin isolated from traditional Chinese medicine Centella asiatica herbs. To gain a deeper understanding of the neuroprotective mechanism of MC against PIMT deficiency-induced neurodegeneration, further studies will be carried out to determine the role of autophagy regulated by miRNA using molecular biology, epigenetics and neuropharmacology technologies in PIMT knockout mice and mouse neuroblastma cell line N2a deficient in PIMT. Our findings will provide scientific basis for MC treatment in neurodegenerative diseases.

脑衰老过程中异天冬氨酸残基(IsoAsp)的形成，可导致神经元代谢异常、降低认知能力及神经退行性疾病的发生。蛋白质异天冬氨酸甲基转移酶(PIMT)能够修复isoAsp。PIMT功能异常与神经退行性疾病发生发展密切相关，但其具体分子机制尚未完全阐明。前期研究发现PIMT缺失引起小鼠大脑中海马齿状回细胞退化、突触蛋白synapsin翻译后修饰改变、氧化应激、自噬和microRNA(miRNAs)紊乱等神经退行性病变。中医药积雪草三萜皂苷类有效组分羟基积雪草苷(MC)能够改善PIMT缺失引起的神经退行性病变。为了进一步探讨MC的神经保护作用机制，本项目拟利用PIMT敲除小鼠和PIMT缺失的小鼠神经瘤母细胞N2a，结合分子生物学、表观遗传学和神经药理学技术，研究miRNAs调控自噬在MC治疗PIMT缺失导致神经退行性病理改变中的作用，为MC成为防治神经退行性疾病新药提供科学依据。

蛋白质异天冬氨酸甲基转移酶(PIMT)功能异常与神经退行性疾病发生发展密切相关，但其具体分子机制尚未完全阐明。前期研究发现PIMT缺失引起小鼠大脑中海马齿状回细胞退变、氧化应激、自噬和microRNA(miRNAs)紊乱等神经退行性病变。中医药积雪草有效组分羟基积雪草苷(MC)能够改善PIMT缺失引起的这些神经病理改变。为了进一步探讨MC的神经保护作用机制，本项目利用PIMT敲除小鼠和PIMT缺失的小鼠神经瘤母细胞N2a，结合分子生物学、表观遗传学和神经药理学技术，发现关键miRNAs分子miR-34a-5通过调控LC3和p62介导的自噬在MC改善PIMT缺失导致神经退行性病变中发挥重要作用，为MC成为防治神经退行性疾病新药研发提供科学依据。