Koyanagi Yukako, Kassai Momoe, Yoneyama Hiroshi
Laboratory of Animal Microbiology, Department of Microbial Biotechnology, Graduate School of Agricultural Science, Tohoku University, Sendai 980-0845, Japan.
Sumitomo Pharma Co., Ltd., Osaka 554-0022, Japan.
Microorganisms. 2024 Jan 5;12(1):106. doi: 10.3390/microorganisms12010106.
Intestinal microbiota and Toll-like receptor 2 (TLR2), which can bind lipoteichoic acid produced by microbiota, might contribute to the pathogenesis of Parkinson's disease (PD), which is characterized by α-synuclein accumulation. Although the contribution of intestinal microbiota and TLR2 to PD pathology was validated in genetic PD models, evidence suggests that the effects of TLR2 signaling on proteinopathy might depend on the presence of a genetic etiology. We examined the impact of intestinal microbiota and TLR2 signaling on α-synuclein pathology in a nontransgenic mouse model of sporadic PD. While an α-synuclein preformed fibrils injection successfully reproduced PD pathology by inducing accumulation of α-synuclein aggregates, microglial activation and increased TLR2 expression in the brains of nontransgenic mice, antibiotic-induced reduction in the density of intestinal microbiota and TLR2 knockout had small impact on these changes. These findings, which are in contrast to those reported in transgenic mice harboring transgene encoding α-synuclein, indicate that the contribution of intestinal microbiota and TLR2 signaling to α-synuclein pathogenesis might be influenced by the presence of a genetic etiology. Additionally, these findings suggest that integrating insights from this experimental model and genetic models would further advance our understanding of the molecular mechanisms underlying sporadic PD.
肠道微生物群和Toll样受体2（TLR2）可结合微生物群产生的脂磷壁酸，它们可能在帕金森病（PD）的发病机制中发挥作用，帕金森病的特征是α-突触核蛋白积聚。尽管在遗传性PD模型中已证实肠道微生物群和TLR2对PD病理的作用，但有证据表明，TLR2信号传导对蛋白病的影响可能取决于遗传病因的存在。我们在散发性PD的非转基因小鼠模型中研究了肠道微生物群和TLR2信号传导对α-突触核蛋白病理的影响。虽然注射α-突触核蛋白预形成纤维通过诱导非转基因小鼠大脑中α-突触核蛋白聚集体的积累、小胶质细胞活化和TLR2表达增加成功再现了PD病理，但抗生素诱导的肠道微生物群密度降低和TLR2基因敲除对这些变化影响较小。这些发现与携带编码α-突触核蛋白转基因的转基因小鼠中报道的结果相反，表明肠道微生物群和TLR2信号传导对α-突触核蛋白发病机制的作用可能受遗传病因存在的影响。此外，这些发现表明，整合来自该实验模型和遗传模型的见解将进一步推动我们对散发性PD潜在分子机制的理解。
