Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Life Sci. 2023 Nov 15;333:122171. doi: 10.1016/j.lfs.2023.122171. Epub 2023 Oct 10.
Parkinson's disease (PD) is a progressive neurodegenerative disorder. The etiology of PD is still elusive but neuroinflammation is proved to be an important contributor. Toll-like receptor 2 (TLR2) involves in the release of several inflammatory cytokines. Whether TLR2 serves as a mediator contributing to the damage of DA system in PD remain unclear.
Tlr2 knockout (Tlr2) and wild-type (WT) mice were treated with a subacute regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At 3, 7 and 14 days after MPTP injection, the behavioral performance, including the Pole test, the Rotarod test, the Rearing test and the Wire hang test was evaluated. Moreover, the PD-like phenotypes, including dopaminergic degeneration, the activation of glial cells and the α-Syn expression were systematically analyzed in the nigrostriatal pathway. Finally, the composition of gut microbiota in the MPTP-treated groups were assessed.
TLR2 deficiency had no obvious impact on the dopaminergic injury at 3 and 7 days following MPTP administration. On the contrary, at 14 days post injection, TLR2 deficiency not only significantly attenuated motor deficits in the Pole test and the Rotarod test, and the nigrostriatal dopaminergic degeneration, but also mitigated α-Syn abnormality, astrocyte activation and neuroinflammation through the suppressed TLR2/MyD88/TRAF6/NF-κB signaling pathways. Additionally, the alteration of gut microbiota was also detected in the mutant mice.
These findings highlight the neuroprotective effect of TLR2-pathways at the late phase in the MPTP-induced PD mouse model.
帕金森病（PD）是一种进行性神经退行性疾病。PD 的病因仍不清楚，但神经炎症已被证明是一个重要的致病因素。Toll 样受体 2（TLR2）参与了几种炎症细胞因子的释放。TLR2 是否作为一种介导物，导致 PD 中 DA 系统的损伤尚不清楚。
用亚急性 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）方案处理 Tlr2 敲除（Tlr2）和野生型（WT）小鼠。在 MPTP 注射后 3、7 和 14 天，评估行为表现，包括棒状试验、转棒试验、站立试验和悬线试验。此外，系统分析黑质纹状体通路中的 PD 样表型，包括多巴胺能神经元变性、神经胶质细胞激活和 α-Syn 表达。最后，评估 MPTP 处理组的肠道微生物群组成。
TLR2 缺失对 MPTP 给药后 3 和 7 天的多巴胺损伤没有明显影响。相反，在注射后 14 天，TLR2 缺失不仅显著减轻了 Pole 试验和转棒试验中的运动缺陷，以及黑质纹状体多巴胺能变性，而且通过抑制 TLR2/MyD88/TRAF6/NF-κB 信号通路，减轻了 α-Syn 异常、星形胶质细胞激活和神经炎症。此外，还检测到突变小鼠肠道微生物群的改变。
这些发现强调了 TLR2 通路在 MPTP 诱导的 PD 小鼠模型后期的神经保护作用。
