Yan Yu-Chen, Su Lu, Zhao Wan-Bing, Fan Yun, Koprich James B, Xiao Bao-Guo, Song Bin, Wang Jian, Yu Wen-Bo
Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China.
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200040, China.
Brain Behav Immun. 2025 Jan;123:1114-1126. doi: 10.1016/j.bbi.2024.10.025. Epub 2024 Oct 24.
Parkinson's disease (PD) pathogenesis is characterized by α-synuclein (α-syn) pathology, which is influenced by various factors such as neuroinflammation and senescence. Increasing evidence has suggested a pivotal role for Interleukin-17A(IL-17A) and Interleukin-17 Receptor A (IL-17RA) in PD, yet the trigger and impact of IL-17A/IL-17RA activation in PD remains elusive. This study observed an age-related increase in IL-17A and IL-17RA in the human central nervous system, accompanied by increased α-syn and senescence biomarkers. Interestingly, both levels of IL-17A and IL-17RA in PD patients were significantly elevated compared to age-matched controls, wherein the IL-17A was mainly present in neurons. This abnormal neuronal IL-17A activation in the PD brain was recapitulated in α-syn mouse models. Correspondingly, administration of recombinant IL-17A exacerbated pathological α-syn in both neuron and mouse models. Furthermore, IL-17A/IL-17RA pathway interventions via blocking antibody or shRNA-mediated knockdown can mitigate the effects of pathological α-syn. This study reveals an interplay between dysregulation of the IL-17A/IL-17RA pathway and α-syn, suggesting that regulating the IL-17A/IL-17RA pathway could modify PD progression by disrupting the detrimental cycle.
帕金森病（PD）的发病机制以α-突触核蛋白（α-syn）病理为特征，其受神经炎症和衰老等多种因素影响。越来越多的证据表明白细胞介素-17A（IL-17A）和白细胞介素-17受体A（IL-17RA）在帕金森病中起关键作用，但IL-17A/IL-17RA激活在帕金森病中的触发因素和影响仍不清楚。本研究观察到人类中枢神经系统中IL-17A和IL-17RA随年龄增长而增加，同时α-syn和衰老生物标志物也增加。有趣的是，与年龄匹配的对照组相比，帕金森病患者的IL-17A和IL-17RA水平均显著升高，其中IL-17A主要存在于神经元中。在α-syn小鼠模型中重现了帕金森病大脑中这种异常的神经元IL-17A激活。相应地，在神经元和小鼠模型中，重组IL-17A的给药都会加重病理性α-syn。此外，通过阻断抗体或shRNA介导的敲低对IL-17A/IL-17RA通路进行干预，可以减轻病理性α-syn的影响。本研究揭示了IL-17A/IL-17RA通路失调与α-syn之间的相互作用，表明调节IL-17A/IL-17RA通路可能通过破坏有害循环来改变帕金森病的进展。
