Zhu Wenzhong, Hu Yuan, Shi Yongping, Bao Haijun, Cheng Xukai, Jiang Mi, Peng Zuojie, Song Jia, Fang Feifei, Jian Chenxing, Yuan Wenzheng, Chen Jinghuang, Shu Xiaogang
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, PR China.
Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No,1277, Wuhan, Hubei 430022, China.
Microbiol Res. 2025 Apr;293:128077. doi: 10.1016/j.micres.2025.128077. Epub 2025 Jan 24.
The interplay between Parkinson's disease (PD) and sleep disturbances suggests that sleep problems constitute a risk factor for PD progression, but the underlying mechanisms remain unclear. Microglial activation and oxidative stress are considered to play an important role in the pathogenesis of aging and neurodegenerative diseases. We hypothesized that sleep deprivation (SD) could exacerbate PD progression via modulating microglial activation and oxidative stress. To test this hypothesis, we established a PD mouse model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), then subjected the mice to SD. A battery of behavioral tests, including rotarod, pole, adhesive removal, and open field tests, were used to assess motor function. Our study showed that SD exacerbated motor deficits, loss of tyrosine hydroxylase (TH), microglial activation and oxidative stress damage in PD model mice. Fecal microbiota transplantation experiments revealed that SD mediated PD progression, microglial activation and oxidative stress via the gut microbiota. 16S rRNA sequencing analysis indicated that SD increased the abundances of bacteria such as Bacteroidaceae, while decreasing the abundances of bacteria including Lactobacillus. Non-targeted metabolomic analysis of gut microbiota-derived metabolites revealed that SD significantly increased the production of adenosine (ADO), a purine metabolite. Probiotic supplementation reversed the effects of SD on motor deficits, dopaminergic neuron loss, microglial activation and oxidative stress damage in PD mice; it also decreased SD-induced ADO production. Administration of Adenosine A2A receptor (A2AR) inhibitors, Istradefylline (Ist), attenuated the roles of SD and ADO in promoting microglial activation, oxidative stress and PD progression. Taken together, our findings indicate that SD accelerates PD progression via regulating microbiota associated microglial activation and oxidative stress, suggesting that efforts to improve sleep quality can be used to prevent and treat PD.
帕金森病（PD）与睡眠障碍之间的相互作用表明，睡眠问题是PD病情进展的一个风险因素，但其潜在机制仍不清楚。小胶质细胞激活和氧化应激被认为在衰老和神经退行性疾病的发病机制中起重要作用。我们假设睡眠剥夺（SD）可通过调节小胶质细胞激活和氧化应激来加剧PD的进展。为了验证这一假设，我们使用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）建立了PD小鼠模型，然后对小鼠进行睡眠剥夺。一系列行为测试，包括转棒试验、杆试验、粘胶去除试验和旷场试验，用于评估运动功能。我们的研究表明，睡眠剥夺加剧了PD模型小鼠的运动缺陷、酪氨酸羟化酶（TH）丧失、小胶质细胞激活和氧化应激损伤。粪便微生物群移植实验表明，睡眠剥夺通过肠道微生物群介导PD进展、小胶质细胞激活和氧化应激。16S rRNA测序分析表明，睡眠剥夺增加了拟杆菌科等细菌的丰度，同时降低了包括乳酸杆菌在内的细菌的丰度。对肠道微生物群衍生代谢物的非靶向代谢组学分析表明，睡眠剥夺显著增加了嘌呤代谢物腺苷（ADO）的产生。补充益生菌可逆转睡眠剥夺对PD小鼠运动缺陷、多巴胺能神经元丧失、小胶质细胞激活和氧化应激损伤的影响；它还降低了睡眠剥夺诱导的ADO产生。给予腺苷A2A受体（A2AR）抑制剂异他林（Ist）可减弱睡眠剥夺和ADO在促进小胶质细胞激活、氧化应激和PD进展中的作用。综上所述，我们的研究结果表明，睡眠剥夺通过调节与微生物群相关的小胶质细胞激活和氧化应激来加速PD进展，这表明改善睡眠质量的努力可用于预防和治疗PD。
