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帕金森氏病(Parkinson’s disease,PD)是由遗传和炎症等多种病因引起的神经退行性疾病。有多种可模拟PD发病的动物模型,α-synuclein(A53T)转基因小鼠和脂多糖(lipopolysaccharide,LPS)腹腔注射小鼠分别从基因突变和炎症角度模拟PD的病理改变,但这些模型仅模拟PD发病的单一因素,且出现病理改变的时间较长。本实验采用LPS注射α-synuclein转基因小鼠建立炎症和遗传因素双重打击的PD模型。结果显示LPS联合α-synuclein转基因刺激可明显引起小鼠运动协调能力和多巴胺神经元功能障碍,以上行为学和病理改变均较二者单独刺激明显加重,表现出协同效应。机制研究发现LPS联合α-synuclein可引起明显的神经炎症和神经元凋亡,差异蛋白质组学研究发现LPS和α-synuclein双重打击可导致小鼠脑中与炎症和凋亡相关蛋白CD99抗原样蛋白2(CD99L2)和细胞色素C氧化酶7A相关蛋白(COX7RP)的表达明显提高,提示这两种蛋白可能参与PD的发病过程。以上研究表明在基因突变基础上引入炎症刺激可建立更理想的PD动物模型。
Parkinson’s disease (PD) is a neurodegenerative disease caused by many causes such as heredity and inflammation. There are a variety of animal models that can simulate the onset of PD. The mice injected intraperitoneally with α-synuclein (A53T) transgenic mice and lipopolysaccharide (LPS) mimics the pathological changes of PD from the perspective of gene mutation and inflammation. However, these models only mimic PD a single factor, and the pathological changes occurred longer. In this study, α-synuclein transgenic mice injected with LPS were used to establish a PD model of double impact of inflammation and genetic factors. The results showed that LPS combined with α-synuclein gene transfection could significantly promote motor coordination and dysfunction of dopaminergic neurons. The above behavioral and pathological changes were significantly aggravated compared with the stimulation of both alone and showed synergistic effects. Mechanistic study found that LPS combined with α-synuclein can cause significant neuroinflammation and neuronal apoptosis. Differential proteomics study found that double impact of LPS and α-synuclein can lead to inflammatory and apoptosis-related protein CD99 antigen-like protein 2 (CD99L2) and cytochrome C oxidase 7A related protein (COX7RP) expression significantly increased, suggesting that these two proteins may be involved in the pathogenesis of PD. The above studies show that introduction of inflammatory stimuli based on gene mutations can establish a more ideal animal model of PD.