Duan Qingrui, Zhang Qingxi, Jiang ShuoLin, Nie Kun, Feng Shujun, Qiu Yihui, He Peikun, Xing Yuxuan, Liu Jiaxuan, Ma Guixian, Zhang Yuhu, Gao Yuyuan, Wang Lijuan
Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People's Republic of China.
Guangzhou Key Laboratory of Diagnosis and Treatment for Neurodegenerative Diseases, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People's Republic of China.
Am J Physiol Cell Physiol. 2025 Mar 1;328(3):C836-C855. doi: 10.1152/ajpcell.00639.2024. Epub 2024 Dec 9.
Parkinson's disease (PD) is an age-related neurodegenerative disorder. The pathological feature of PD is abnormal α-synuclein (α-syn) formation and transmission. Recent evidence demonstrates that α-syn preformed fibrils (α-syn PFFs) can be detected in the serum of patients with PD. The peripheral blood α-syn PFF can cross the blood-brain barrier (BBB) and aggravate neuronal damage, but the mechanism remains to be elucidated. We constructed the PD mouse models of different severity: the mild pathology (A53T ONLY) and the severe pathology (A53T + Brain FIB); this was followed by α-syn PFFs intravenous injection. Then, we used endothelium-specific Lag3 knockout mice (Lag3-ECs-CKO) to decrease the blood α-syn PFFs spreading. We observed that intravenous transmission of α-syn PFFs significantly aggravated motor deficits, dopaminergic neuron loss, neuroinflammation, and pathologic α-syn deposition in A53T ONLY, but not in A53T + Brain FIB. Blocking endothelial Lag3 endocytosis by Lag3-ECs-CKO decreased the blood α-syn PFFs spreading and improved the symptoms and pathogenesis of PD mice. Our findings reveal the role of peripheral blood α-syn PFFs transmission in the mild pathology or early-stage PD and the mechanism of endothelial Lag3 endocytosis in the pathology of α-syn transmission. Targeting endothelial Lag3 to prevent α-syn from spreading from the blood to the brain may be a disease-modifying therapy in early-stage PD. This study highlights the transmission mechanism of peripheral blood α-synuclein preformed fibrils (α-syn PFFs) through endothelial Lag3 endocytosis in the mild pathology or early-stage Parkinson's disease (PD). Targeting endothelial Lag3 as a perspective of decreasing peripheral blood α-syn PFFs transmission may be a disease-modifying therapy in early-stage PD.
帕金森病（PD）是一种与年龄相关的神经退行性疾病。PD的病理特征是α-突触核蛋白（α-syn）异常形成和传播。最近的证据表明，在PD患者的血清中可以检测到α-突触核蛋白原纤维（α-syn PFFs）。外周血α-syn PFFs可穿过血脑屏障（BBB）并加重神经元损伤，但其机制仍有待阐明。我们构建了不同严重程度的PD小鼠模型：轻度病理模型（仅A53T）和重度病理模型（A53T + 脑纤维）；随后进行α-syn PFFs静脉注射。然后，我们使用内皮细胞特异性Lag3基因敲除小鼠（Lag3-ECs-CKO）来减少血液中α-syn PFFs的传播。我们观察到，α-syn PFFs的静脉内传播显著加重了仅A53T模型小鼠的运动功能障碍、多巴胺能神经元丢失、神经炎症和病理性α-syn沉积，但在A53T + 脑纤维模型小鼠中未出现这种情况。通过Lag3-ECs-CKO阻断内皮细胞Lag3内吞作用可减少血液中α-syn PFFs的传播，并改善PD小鼠的症状和发病机制。我们的研究结果揭示了外周血α-syn PFFs传播在轻度病理或早期PD中的作用，以及内皮细胞Lag3内吞作用在α-syn传播病理过程中的机制。靶向内皮细胞Lag3以防止α-syn从血液扩散到大脑可能是早期PD的一种疾病修饰疗法。本研究强调了在轻度病理或早期帕金森病（PD）中，外周血α-突触核蛋白原纤维（α-syn PFFs）通过内皮细胞Lag3内吞作用的传播机制。将靶向内皮细胞Lag3作为减少外周血α-syn PFFs传播的一个研究方向，可能是早期PD的一种疾病修饰疗法。
