Abstract:
The pathological hallmark of Parkinson\'s disease (PD) is the intraneuronal accumulation of misfolded alpha-synuclein (termed Lewy bodies) in dopaminergic neurons of substantia nigra par compacta (SNc). It is assumed that the α-syn pathology is induced by gastrointestinal inflammation and then transfers to the brain by the gut-brain axis. Therefore, the relationship between gastrointestinal inflammation and α-syn pathology leading to PD remains to be investigated. In our study, rotenone (ROT) oral administration induces gastrointestinal tract (GIT) inflammation in mice. In addition, we used pseudorabies virus (PRV) for tracing studies and performed behavioral testing. We observed that ROT treatments enhance macrophage activation, inflammatory mediator expression, and α-syn pathology in the GIT 6-week post-treatment (P6). Moreover, pathological α-syn was localized with IL-1R1 positive neural cells in GIT. In line with these findings, we also find pS129-α-syn signals in the dorsal motor nucleus of the vagus (DMV) and tyrosine hydroxylase in the nigral-striatum dynamically change from 3-week post-treatment (P3) to P6. Following that, pS129-α-syn was dominant in the enteric neural cell, DMV, and SNc, accompanied by microglial activation, and these phenotypes were absent in IL-1R1r/r mice. These data suggest that IL-1β/IL-1R1-dependent inflammation of GIT can induce α-syn pathology, which then propagates to the DMV and SNc, resulting in PD.
摘要:
帕金森病(PD)的病理标志是黑质致密质(SNc)多巴胺能神经元内错误折叠的α-突触核蛋白(称为路易体)的神经内积累。假定α-syn病理是由胃肠道炎症引起的,然后通过肠-脑轴转移到大脑。因此,胃肠道炎症与导致PD的α-syn病理之间的关系仍有待研究。在我们的研究中,鱼藤酮(ROT)口服给药诱导小鼠胃肠道(GIT)炎症。此外,我们使用伪狂犬病病毒(PRV)进行追踪研究,并进行行为测试.我们观察到ROT处理增强了巨噬细胞的活化,炎症介质表达,和GIT治疗后6周的α-syn病理学(P6)。此外,病理α-syn在GIT中有IL-1R1阳性神经细胞。根据这些发现,我们还发现迷走神经背侧运动核中的pS129-α-syn信号(DMV)和黑质纹状体中的酪氨酸羟化酶从治疗后3周(P3)到P6动态变化。在此之后,pS129-α-syn在肠神经细胞中占优势,车管所,和SNc,伴随着小胶质细胞激活,这些表型在IL-1R1r/r小鼠中不存在。这些数据表明,IL-1β/IL-1R1依赖的GIT炎症可以诱导α-syn病理,然后传播到DMV和SNc,导致PD。