应用异时联体共生模型探讨LAG-3免疫失调介导的α-synuclein朊蛋白样传播机制

免疫紊乱及炎症反应导致α-syn聚集和传播是PD发生、发展的重要原因。我们及国际研究发现：①CD4+细胞上调免疫调节基因LAG-3表达水平；②该基因突变增加PD罹患风险，患者基底节区LAG-3表达升高；③铁及LAG-3对α-syn朊蛋白样传播起重要介导作用；④注射α-syn聚集体，LAG-3-/-小鼠发生行为学改变，中脑DA神经元变性及小胶质细胞激活（J Neurochem2018，J Neuroinflam2019），推测LAG-3全面参与了α-syn朊蛋白样传播机制。但LAG-3 KO敲除鼠不能真实反映循环α-syn对PD发生、发展的真实影响，而联体共生模型可观察共生小鼠的病理学变化，克服单一模型对疾病机制的局限性理解。为此，本项目针对疾病特点，基于既往基础，拟在临床及细胞生物学研究的同时，应用异时联体共生模型，观察LAG-3介导α-syn传播对PD的病理学影响，进一步揭示其发病机制。

Immune dysfunction and neural inflammation lead to α-syn aggregation and transmission, which play important roles in the development of Parkinson's disease (PD). Both international and our studies showed that: 1) CD4+ cells upregulates the expression level of immunoregulatory gene LAG-3; 2) LAG-3 mutations increased the risk of PD and LAG-3 level in basal ganglia of PD patients; 3) iron and LAG-3 moleculars promote the prion-like transmission of α-syn between cells; 4) LAG-3-/- mice which received α-syn aggregates injection exhibited neurobehavioral dysfunction, dopaminergic neuron degeneration in their midbrain and presented microglia activation in brain tissue, suggesting that LAG-3 involves in α-syn transmission by multiple pathways. However, LAG-3-/- mice are unable to fully reflect the transmission effect of blood α-syn on CNS cells-transmission. Parabiosis experimental models can indicate the pathology of the parabiotic mice, which overcome the defects of regular animal models to reveal the pathological mechanism. Based on the disease feature and our previous study data, here we are going to observe the effect of LAG-3 mediating α-syn transmission on PD pathology via heterochronic parabiosis experimental models as well as to reveal the real mechanism with our clinical and cell biological research.