Olfactory dysfunction is one of the early symptoms seen in Parkinson’s disease (PD). However, the mechanisms underlying olfactory pathology that impacts PD disease progression and post‐mortem appearance of alpha‐Synuclein (α‐Syn) inclusions in and beyond olfactory bulb in PD remain unclear. It has been suggested that environmental toxins inhaled through the nose can induce inflammation in the olfactory bulb (OB), where Lewy body (LB) is the first to be found, and then, spread to related brain regions. We hypothesize that OB inflammation triggers local α‐Syn pathology and promotes its spreading to cause PD. In this study, we evaluated this hypothesis by intranasal infusion of lipopolysaccharides (LPS) to induce OB inflammation in mice and examined cytokines expression and PD‐like pathology. We found intranasal LPS‐induced microglia activation, inflammatory cytokine expression and α‐Syn overexpression and aggregation in the OB via interleukin‐1β (IL‐1β)/IL‐1 receptor type I (IL‐1R1) dependent signaling. In addition, an aberrant form of α‐Syn, the phosphorylated serine 129 α‐Syn (pS129 α‐Syn), was found in the OB, substantia nigra (SN) and striatum 6 weeks after the LPS treatment. Moreover, 6 weeks after the LPS treatment, mice showed reduced SN tyrosine hydroxylase, decreased striatal dopaminergic metabolites and PD‐like behaviors. These changes were blunted in IL‐1R1 deficient mice. Further studies found the LPS treatment inhibited IL‐1R1‐dependent autophagy in the OB. These results suggest that IL‐1β/IL‐1R1 signaling in OB play a vital role in the induction and propagation of aberrant α‐Syn, which may ultimately trigger PD pathology.

中文翻译：

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由鼻内脂多糖输注诱导的 IL-1β/IL-1R1 信号传导调节嗅球、黑质和纹状体中的 α-突触核蛋白病理。

嗅觉功能障碍是帕金森病 (PD) 的早期症状之一。然而，影响 PD 疾病进展和 PD 中嗅球内外的 α-突触核蛋白 (α-Syn) 内含物的死后外观的嗅觉病理学机制仍不清楚。有人提出，通过鼻子吸入的环境毒素会引起嗅球 (OB) 的炎症，在那里首先发现路易体 (LB)，然后扩散到相关的大脑区域。我们假设 OB 炎症会触发局部 α-Syn 病理并促进其扩散导致 PD。在这项研究中，我们通过鼻内输注脂多糖 (LPS) 以诱导小鼠 OB 炎症来评估这一假设，并检查细胞因子表达和 PD 样病理。我们发现鼻内 LPS 诱导的小胶质细胞激活，通过白细胞介素-1β（IL-1β）/IL-1 受体 I 型（IL-1R1）依赖性信号传导在 OB 中炎症细胞因子表达和 α-Syn 过表达和聚集。此外，在 LPS 治疗 6 周后，在 OB、黑质 (SN) 和纹状体中发现了异常形式的 α-Syn，磷酸化丝氨酸 129 α-Syn (pS129 α-Syn)。此外，LPS 治疗后 6 周，小鼠表现出 SN 酪氨酸羟化酶降低、纹状体多巴胺能代谢物和 PD 样行为减少。这些变化在 IL-1R1 缺陷小鼠中减弱。进一步的研究发现 LPS 治疗抑制了 OB 中 IL-1R1 依赖性自噬。这些结果表明 OB 中的 IL-1β/IL-1R1 信号传导在异常 α-Syn 的诱导和传播中起着至关重要的作用，这可能最终引发 PD 病理。