基于α-synuclein PFF脑内注射猴模型探索LAG3基因敲除对自体移植干细胞保护研究

帕金森病（PD）是第二常见的神经退行性疾病，α-突触核蛋白(α-synuclein, α-Syn )异常聚集与帕金森病发病密切相关，但作用机制仍不十分清楚。本课题组前期研究结果证实，受体蛋白LAG3能与α-Syn pre-formed fibrils（α-Syn PFF）选择性结合，并导致α-Syn PFF在神经元间传播。基于上述认识和研究基础，我们提出“通过基因编辑技术敲除移植细胞的LAG3基因，可阻断α-Syn PFF由移植部位宿主细胞传播到移植细胞，从而减轻α-Syn PFF对移植细胞的神经毒性”这一新的科学假设。为证明该科学假设，本课题将首先建立α-Syn PFF脑内神经元间传播猴模型，然后利用该模型结合体内外实验，进一步研究敲除移植细胞的LAG3基因，是否可以减轻α-Syn PFF对移植细胞的神经毒性，并探讨相关机制。本课题研究成果有望为PD的临床治疗提供新的治疗策略。

Parkinson’s disease (PD) is the second most common neurodegenerative disorder，and the abnormal accumulation of the α−synuclein protein in the brain is associated with PD. To date, in vivo pathophysiological mechanisms of a-Syn aggregation are still unclear in PD. In the previous study, we have demonstrated that pathologic α-synuclein transmission and toxicity is initiated by binding to LAG3. Based on those work, we hypothesize that pathologic α-synuclein transmission and neurotoxicity can be attenuated by LAG-3 disruption in engrafted neurons. To test the hypothesis, this study will developed a nonhuman primate α-Syn PFF transmission model by intracerebral injection of α-syn PFF injection, and we will further explore whether pathologic α-synuclein neurotoxicity can be attenuated by deletion of LAG-3 in the implanted cells. Our study may provide a novel therapeutic strategy against PD.