Cyr Brianna, Vontell Regina T, Hadad Roey, de Rivero Vaccari Juan Pablo, Keane Robert W
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Neurology, University of Miami Brain Endowment Bank, University of Miami Miller School of Medicine, Miami, FL, USA.
NPJ Parkinsons Dis. 2025 Apr 25;11(1):92. doi: 10.1038/s41531-025-00963-8.
Parkinson's disease (PD) is associated with chronic sterile inflammation and persistent inflammasome activation involving α-synuclein and ASC protein aggregates, but the underlying mechanisms of the neuroinflammatory response remain unclear. Here, we used midbrain postmortem samples from donors with and without α-synucleinopathies to assess the expression of inflammasome proteins in patients with Parkinsonism. We show that dopaminergic neurons exhibit increased expression of ASC, NOD-like receptor protein (NLRP) 1, and modification of α-synuclein phosphorylation at serine129 (pS129) within the Lewy body inclusions, whereas NLRP3 was identified mainly in microglial. Moreover, treatment of LRRK2 cells with ASC specks from PD and Lewy body dementia patients induced inflammasome activation and cytotoxicity that was blocked by IC100. Administration of preformed α-synuclein aggregates to microglia resulted in a significant elevation in pS129, and this effect was also blocked by IC100. Thus, IC100 may be a promising therapeutic strategy for inflammatory disease modification in synucleinopathies and other diseases.
帕金森病（PD）与慢性无菌性炎症以及涉及α-突触核蛋白和ASC蛋白聚集体的持续性炎性小体激活有关，但神经炎症反应的潜在机制仍不清楚。在此，我们使用来自有无α-突触核蛋白病供体的中脑死后样本，评估帕金森综合征患者炎性小体蛋白的表达。我们发现，多巴胺能神经元中ASC、NOD样受体蛋白（NLRP）1的表达增加，路易小体包涵体内的α-突触核蛋白丝氨酸129位点（pS129）的磷酸化修饰增加，而NLRP3主要在小胶质细胞中被识别。此外，用来自帕金森病和路易体痴呆患者的ASC斑点处理LRRK2细胞可诱导炎性小体激活和细胞毒性，而IC100可阻断这种作用。将预先形成的α-突触核蛋白聚集体给予小胶质细胞会导致pS129显著升高，这种作用也可被IC100阻断。因此，IC100可能是一种有前景的治疗策略，用于改善突触核蛋白病和其他疾病中的炎症性疾病。
