Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211116, China.
J Neuroinflammation. 2023 Feb 14;20(1):36. doi: 10.1186/s12974-023-02720-1.
Increasing evidence suggests that patients with Parkinson's disease (PD) present with peripheral autonomic dysfunction (AutD) that even precedes motor deficits, through which α-synuclein can spread to the central nervous system. However, the pathological mechanisms underlying AutD in prodromal PD remain unclear. Here, we investigated the role of α-synuclein and its interplay with the activation of Schwann cells (SCs) of the vagus nerve in AutD.
Rats were subjected to injection with adeno-associated viruses containing the human mutated A53T gene (AAV-A53T) or an empty vector into the left cervical vagus nerve and evaluated for gastrointestinal symptoms, locomotor functions, intestinal blood flow, and nerve electrophysiology. Further, we examined the impact of α-synucleinopathy on vagus nerves, SCs, and central nervous system neurons using electron microscopy, immunofluorescence, immunohistochemistry, and western blot. Finally, the role of Toll-like receptor 2 (TLR2) in regulating the neuroinflammation in the vagus nerve via MyD88 and NF-κB pathway was determined using genetic knockdown.
We found that rats injected with AAV-A53T in the vagus nerve exhibited prominent signs of AutD, preceding the onset of motor deficits and central dopaminergic abnormalities by at least 3 months, which could serve as a model for prodromal PD. In addition, reduced intestinal blood flow and decreased nerve conduction velocity were identified in AAV-A53T-injected rats, accompanied by disrupted myelin sheaths and swollen SCs in the vagus nerve. Furthermore, our data demonstrated that p-α-synuclein was deposited in SCs but not in axons, activating the TLR2/MyD88/NF-κB signaling pathway and leading to neuroinflammatory responses. In contrast, silencing the TLR2 gene not only reduced inflammatory cytokine expression but also ameliorated vagal demyelination and secondary axonal loss, consequently improving autonomic function in rats.
These observations suggest that overexpression of α-synuclein in the vagus nerve can induce symptoms of AutD in prodromal PD, and provide support for a deeper understanding of the pathological mechanisms underlying AutD and the emergence of effective therapeutic strategies for PD.
越来越多的证据表明，帕金森病（PD）患者存在外周自主神经功能障碍（AutD），甚至在运动缺陷之前就已经出现，通过这种方式，α-突触核蛋白可以传播到中枢神经系统。然而，前驱期 PD 中 AutD 的病理机制尚不清楚。在这里，我们研究了α-突触核蛋白及其与迷走神经施万细胞（SCs）激活之间的相互作用在 AutD 中的作用。
将携带人突变 A53T 基因的腺相关病毒（AAV-A53T）或空载体注入大鼠左侧颈迷走神经，评估其胃肠道症状、运动功能、肠道血流和神经电生理学。此外，我们使用电子显微镜、免疫荧光、免疫组织化学和 Western blot 检查α-突触核蛋白病对迷走神经、SCs 和中枢神经系统神经元的影响。最后，通过 MyD88 和 NF-κB 通路，使用遗传敲低确定 Toll 样受体 2（TLR2）在调节迷走神经神经炎症中的作用。
我们发现，在迷走神经中注射 AAV-A53T 的大鼠表现出明显的 AutD 迹象，至少提前 3 个月出现运动缺陷和中枢多巴胺能异常，可作为前驱期 PD 的模型。此外，在 AAV-A53T 注射大鼠中发现肠道血流减少和神经传导速度降低，伴迷走神经 SCs 髓鞘破坏和肿胀。此外，我们的数据表明，p-α-突触核蛋白沉积在 SCs 中，而不在轴突中，激活 TLR2/MyD88/NF-κB 信号通路，导致神经炎症反应。相反，沉默 TLR2 基因不仅减少了炎症细胞因子的表达，还改善了迷走神经脱髓鞘和继发性轴突丢失，从而改善了大鼠的自主功能。
这些观察结果表明，迷走神经中α-突触核蛋白的过度表达可引起前驱期 PD 中的 AutD 症状，并为深入了解 AutD 的病理机制以及为 PD 提供有效的治疗策略提供支持。
