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The Impact of Intestinal Microbiota and Toll-like Receptor 2 Signaling on α-Synuclein Pathology in Nontransgenic Mice
Yukako Koyanagi1,2, Momoe Kassai2, Hiroshi Yoneyama1
1Laboratory of Animal Microbiology, Department of Microbial Biotechnology, Graduate School of Agricultural Science, Tohoku University, Sendai 980-0845, Japan.
Abstract:
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.
Insights
Gut bacteria and Toll-like receptor 2 (TLR2) may influence Parkinson's disease (PD). However, their impact on alpha-synuclein pathology in non-genetic models is minimal, suggesting a role for genetic factors.
Area of Science:
- Neuroscience
- Immunology
- Microbiology
Background:
- Parkinson's disease (PD) involves alpha-synuclein accumulation.
- Intestinal microbiota and Toll-like receptor 2 (TLR2) are implicated in PD pathogenesis, particularly in genetic models.
- The role of TLR2 signaling in proteinopathy may depend on genetic factors.
Purpose of the Study:
- To investigate the impact of intestinal microbiota and TLR2 signaling on alpha-synuclein pathology in a non-transgenic mouse model of sporadic PD.
- To determine if reducing intestinal microbiota or knocking out TLR2 affects PD pathology in this model.
Main Methods:
- Utilized a non-transgenic mouse model of sporadic Parkinson's disease.
- Induced PD pathology via alpha-synuclein preformed fibrils injection.
- Administered antibiotics to reduce intestinal microbiota density.
- Examined the effect of TLR2 knockout.
Main Results:
- Alpha-synuclein aggregate accumulation, microglial activation, and increased brain TLR2 expression were observed after alpha-synuclein injection in non-transgenic mice.
- Antibiotic treatment and TLR2 knockout had minimal effects on these pathological changes.
- Findings contrast with those in genetic PD models.
Conclusions:
- Intestinal microbiota and TLR2 signaling appear to have a limited role in the pathogenesis of alpha-synuclein pathology in sporadic PD without a genetic etiology.
- Genetic factors likely influence the contribution of the gut microbiota and TLR2 to PD pathogenesis.
- Further research combining insights from genetic and non-genetic models is needed to understand sporadic PD mechanisms.
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