帕金森病关键基因α-synuclein对多巴胺神经元末梢局部蛋白表达的调控研究

帕金森病(PD)是中老年人常见的神经系统变性疾病。已有的患者尸检病理数据显示，α-突触核蛋白是PD病变特征路易小体的主要成分。并有实验表明该蛋白及突变体会首先在多巴胺(DA)神经元的末梢异常聚集，而后逆行导致胞体的变性，即其轴突变性先于胞体变性。但如何导致该轴突变性的分子机制还尚未清楚。我们基于已有研究首次提出了α-突触核蛋白突变体可能通过干扰DA神经元轴突末梢局部蛋白的正常表达，而诱发了轴突变性的假说。为验证该假说本项目以已构建的α-突触核蛋白A53T过表达PD小鼠为基础，以核糖体免疫共沉淀(TRAP)技术为核心，拟通过高通量测序获得轴突局部mRNAs的表达图谱，继而应用生物信息学手段得到A53T组与对照组差异表达的基因及相关通路，来进一步了解α-突触核蛋白的突变体是如何通过改变轴突末梢局部蛋白的表达而诱发轴突变性的。本项目进一步探索了轴突变性机制，为PD病理成因及药物研发提供了新线索。

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy body. With the advent of global aging, the number of PD patients grows faster especially in China. α-Synuclein is the main component of Lewy bodies. Whereas both missense (such as A53T) and multiplication mutations of α-synuclein can cause the early-onset autosomal dominant familial form of PD. Previous studies indicated that the mice with expressing human A53T mutant showed α-synuclein aggregates at the presynapses of Dopaminergic (DA) neurons, where it physiologically located. Importantly, in some PD-like mouse models, such abnormal aggregation caused the axon degeneration first and soma degeneration later on. However the mechanism that underlines this interesting phenomenon is still unclear. Based on previous studies, we proposed that the overexpression of α-synuclein A53T may first disrupt the local translation of axon terminals in dopaminergic neurons, and lead to the axon degeneration afterwards. To address this hypothesis, a new technology TRAP was applied, through which mRNAs with high activity can be obtained. After comparing the mRNA expression profiles from axon terminals between control and A53T mouse model, the differentially expressed genes would be identified. To study these candidate genes and related pathways, we can better know how a-synuclein regulates the local translation of the axon terminals in DA neurons, which may be directly related with the axon degeneration.