药学学报, 2017, 52(5): 729-736
引用本文:
郑远鹏, 臧彩霞, 王璐, 杨瀚宇, 孙华, 鲍秀琦, 张丹. 脂多糖加重α-synuclein基因突变小鼠多巴胺能神经元损伤机制的研究[J]. 药学学报, 2017, 52(5): 729-736.
ZHENG Yuan-peng, ZANG Cai-xia, WANG Lu, YANG Han-yu, SUN Hua, BAO Xiu-qi, ZHANG Dan. Lipopolysaccharide potentiates dopaminergic neuronal dysfunction in α-synuclein transgenic mice[J]. Acta Pharmaceutica Sinica, 2017, 52(5): 729-736.

脂多糖加重α-synuclein基因突变小鼠多巴胺能神经元损伤机制的研究
郑远鹏, 臧彩霞, 王璐, 杨瀚宇, 孙华, 鲍秀琦, 张丹
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
摘要:
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。
关键词:    帕金森氏病      脂多糖      α-突触核蛋白      神经炎症     
Lipopolysaccharide potentiates dopaminergic neuronal dysfunction in α-synuclein transgenic mice
ZHENG Yuan-peng, ZANG Cai-xia, WANG Lu, YANG Han-yu, SUN Hua, BAO Xiu-qi, ZHANG Dan
State Key Laboratory of Natural Products and Functions, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Parkinson's disease (PD) is the most prevalent neurodegenerative disorder, with several risk factors contributing to the onset, such as aging, genetics, oxidative stress and neuroinflammation. There are several PD animals that mimics different risk factor. α-Synuclein mutation mice and systemic lipopolysaccharide (LPS) injection mice are two kinds of most common animal models that replicate genetic mutation and neuroinflammation, respectively. However, in these two animal models, the pathogenesis occurred after a long period of stimulation. In the present study, four-month-old α-synucleintransgenic mice (A53T) were intraperitoneally injected with LPS once a week for continuous 8 weeks to simulate the inflammatory response. The behavioral results showed that the time of mice staying on the rod and the performance score were markedly decreased, indicating motor dysfunction. Dopaminergic neuronal function also decreased. It was noted that the movement dysfunction and pathological changes were aggravated in LPS plus α-synuclein challenged mice compared with LPS or α-synuclein stimulated alone, suggesting that the double attack had synergistic effects. Mechanistic study demonstrated that LPS and α-synuclein combined challenge led to obvious neuroinflammatory response and apoptosis, which might contribute to motor and dopaminergic neuronal dysfunction. In addition, differential proteomic study showed that the expression of CD99L2 and COX7RP significantly increased in the midbrain of LPS plus α-synuclein challenged mice, which were closely related to inflammation and apoptosis, and might be involved in the pathogenesis of PD. In conclusion, the present study demonstrated that LPS could potentiate dopaminergic neuronal function in α-synuclein transgenic mice, which might be an ideal method to develop PD animal model.
Key words:    Parkinson's disease    lipopolysaccharide    α-synuclein    neuroinflammation   
收稿日期: 2017-01-16
DOI: 10.16438/j.0513-4870.2017-0065
基金项目: 国家自然科学基金资助项目(81630097);中国医学科学院医学与健康科技创新工程资助项目(2016-I2M-3-011).
通讯作者: 鲍秀琦,Tel:86-10-63165178,E-mail:baoxiuqi@imm.ac.cn;张丹,Tel:86-10-63165203,E-mail:danzhang@imm.ac.cn
Email: baoxiuqi@imm.ac.cn;danzhang@imm.ac.cn
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