Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Proc Natl Acad Sci U S A. 2021 Apr 13;118(15). doi: 10.1073/pnas.2025847118.
Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.
帕金森病的特征是α-突触核蛋白（αSyn）的积累。受损神经元中寡聚/纤维状αSyn 的释放可能会通过小胶质细胞的激活而增强神经元死亡。迄今为止，尚不清楚寡聚/纤维状αSyn 是否可以在人类小胶质细胞中激活核苷酸结合寡聚化结构域（NOD）样受体（NLR）家族富含pyrin 结构域的 3（NLRP3）炎性体，以及抗αSyn 抗体是否可以预防这种作用。在这里，我们表明 αSyn 通过涉及 Toll 样受体 2（TLR2）参与和线粒体损伤的双重刺激，在人诱导多能干细胞（hiPSC）衍生的小胶质细胞（hiMG）中激活 NLRP3 炎性体。在体外，hiMG 可被 hiPSC 衍生的 A9-多巴胺能神经元分泌的突变（A53T）αSyn 激活。令人惊讶的是，αSyn-抗体复合物增强而不是抑制炎性体介导的白细胞介素 1β（IL-1β）分泌，表明这些复合物在人类环境中具有神经炎症作用。与寡聚淀粉样β肽（Aβ）及其同源抗体一起添加时，会观察到炎症进一步增加。在体内，将携带 αSyn 的 hiMG 植入人源化小鼠大脑中会导致半胱天冬酶-1 的激活和神经毒性，而αSyn 抗体则会加剧这种毒性。这些发现对于旨在从人脑中耗尽错误折叠/聚集蛋白的抗体疗法可能具有重要意义，因为它们可能会在人类小胶质细胞中引发炎症。
