Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder and is characterized by the formation of cellular inclusions inside neurons that are rich in an abnormal form of the protein α-synuclein (α-syn). Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of signaling transduction pathways. Here, we studied activation of primary microglia isolated from wild-type mouse by distinct α-syn forms and their clearance. Internalization of α-syn monomers and oligomers efficiently activated the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome via TLR2 and TLR5 ligation, thereby acting on different signaling checkpoints. We found that primary microglia effectively engulf α-syn but hesitate in its degradation. NLRP3 inhibition by the selective inhibitor CRID3 sodium salt and NLRP3 deficiency improved the overall clearance of α-syn oligomers. Together, these data show that distinct α-syn forms exert different microglial NLRP3 inflammasome activation properties, thereby compromising its degradation, which can be prevented by NLRP3 inhibition.

帕金森病 (PD) 是第二种最常见的与年龄相关的神经退行性疾病，其特征是在神经元内形成细胞内含物，这些内含物富含异常形式的蛋白质 α-突触核蛋白 (α-syn)。小胶质细胞是 CNS 常驻免疫细胞，通过模式识别受体连接和信号转导通路的激活对错误折叠的蛋白质作出反应。在这里，我们研究了不同 α-syn 形式对从野生型小鼠分离的初级小胶质细胞的激活及其清除。α-syn 单体和寡聚体的内化通过 TLR2 和 TLR5 连接有效地激活了包含 3 (NLRP3) 炎症小体的 NOD 样受体 pyrin 结构域，从而作用于不同的信号检查点。我们发现初级小胶质细胞有效地吞噬了 α-syn，但对其降解犹豫不决。选择性抑制剂 CRID3 钠盐和 NLRP3 缺陷对 NLRP3 的抑制提高了 α-syn 寡聚体的整体清除率。总之，这些数据表明不同的 α-syn 形式发挥不同的小胶质细胞 NLRP3 炎症小体激活特性，从而影响其降解，这可以通过 NLRP3 抑制来防止。