Wang Hualong, Chen Guiqin, Ahn Eun Hee, Xia Yiyuan, Kang Seong Su, Liu Xia, Liu Chang, Han Ming-Hu, Chen Shengdi, Ye Keqiang
Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
Department of Neurology, The First Hospital of Hebei Medical University (Department of Neurology, Hebei Hospital of Xuanwu Hospital Capital Medical University), Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, 050031, Hebei, P. R. China.
NPJ Parkinsons Dis. 2023 Jan 6;9(1):1. doi: 10.1038/s41531-022-00430-8.
Parkinson's disease (PD) is the most common neurodegenerative motor disorder, and its pathologic hallmarks include extensive dopaminergic neuronal degeneration in the Substantia nigra associated with Lewy bodies, predominantly consisting of phosphorylated and truncated α-Synuclein (α-Syn). Asparagine endopeptidase (AEP) cleaves human α-Syn at N103 residue and promotes its aggregation, contributing to PD pathogenesis. However, how AEP mediates Lewy body pathologies during aging and elicits PD onset remains incompletely understood. Knockout of AEP or C/EBPβ from α-SNCA mice, and their chronic rotenone exposure models were used, and the mechanism of α-Syn from the gut that spread to the brain was observed. Here we report that C/EBPβ/AEP pathway, aggravated by oxidative stress, is age-dependently activated and cleaves α-Syn N103 and regulates Lewy body-like pathologies spreading from the gut into the brain in human α-SNCA transgenic mice. Deletion of C/EBPβ or AEP substantially diminished the oxidative stress, neuro-inflammation, and PD pathologies, attenuating motor dysfunctions in aged α-SNCA mice. Noticeably, PD pathologies initiate in the gut and progressively spread into the brain. Chronic gastric exposure to a low dose of rotenone initiates Lewy body-like pathologies in the gut that propagate into the brain in a C/EBPβ/AEP-dependent manner. Hence, our studies demonstrate that C/EBPβ/AEP pathway is critical for mediating Lewy body pathology progression in PD.
帕金森病（PD）是最常见的神经退行性运动障碍，其病理特征包括黑质中与路易小体相关的广泛多巴胺能神经元变性，路易小体主要由磷酸化和截短的α-突触核蛋白（α-Syn）组成。天冬酰胺内肽酶（AEP）在N103残基处切割人α-Syn并促进其聚集，导致PD发病机制。然而，AEP如何在衰老过程中介导路易小体病理并引发PD发病仍不完全清楚。使用从α-SNCA小鼠中敲除AEP或C/EBPβ及其慢性鱼藤酮暴露模型，观察了α-Syn从肠道扩散到大脑的机制。我们在此报告，在人α-SNCA转基因小鼠中，由氧化应激加剧的C/EBPβ/AEP途径在年龄依赖性激活时切割α-Syn N103并调节从肠道扩散到大脑的路易小体样病理。删除C/EBPβ或AEP可显著减轻氧化应激、神经炎症和PD病理，减轻老年α-SNCA小鼠的运动功能障碍。值得注意的是，PD病理始于肠道并逐渐扩散到大脑。慢性胃内低剂量鱼藤酮暴露可引发肠道内路易小体样病理，并以C/EBPβ/AEP依赖的方式传播到大脑。因此，我们的研究表明，C/EBPβ/AEP途径对于介导PD中路易小体病理进展至关重要。
