Bayati Armin, Ayoubi Riham, Aguila Adriana, Zorca Cornelia E, Deyab Ghislaine, Han Chanshuai, Recinto Sherilyn Junelle, Nguyen-Renou Emmanuelle, Rocha Cecilia, Maussion Gilles, Luo Wen, Shlaifer Irina, Banks Emily, McDowell Ian, Del Cid Pellitero Esther, Ding Xue Er, Sharif Behrang, Séguéla Philippe, Yaqubi Moein, Chen Carol X-Q, You Zhipeng, Abdian Narges, McBride Heidi M, Fon Edward A, Stratton Jo Anne, Durcan Thomas M, Nahirney Patrick C, McPherson Peter S
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
The Neuro's Early Drug Discovery Unit (EDDU), McGill University, Montreal, QC, Canada.
Nat Neurosci. 2024 Dec;27(12):2401-2416. doi: 10.1038/s41593-024-01775-4. Epub 2024 Oct 8.
Lewy bodies (LBs), α-synuclein-enriched intracellular inclusions, are a hallmark of Parkinson's disease (PD) pathology, yet a cellular model for LB formation remains elusive. Recent evidence indicates that immune dysfunction may contribute to the development of PD. In this study, we found that induced pluripotent stem cell (iPSC)-derived human dopaminergic (DA) neurons form LB-like inclusions after treatment with α-synuclein preformed fibrils (PFFs) but only when coupled to a model of immune challenge (interferon-γ or interleukin-1β treatment) or when co-cultured with activated microglia-like cells. Exposure to interferon-γ impairs lysosome function in DA neurons, contributing to LB formation. The knockdown of LAMP2 or the knockout of GBA in conjunction with PFF administration is sufficient for inclusion formation. Finally, we observed that the LB-like inclusions in iPSC-derived DA neurons are membrane bound, suggesting that they are not limited to the cytoplasmic compartment but may be formed due to dysfunctions in autophagy. Together, these data indicate that immune-triggered lysosomal dysfunction may contribute to the development of PD pathology.
路易小体（LBs）是富含α-突触核蛋白的细胞内包涵体，是帕金森病（PD）病理的一个标志，但路易小体形成的细胞模型仍然难以捉摸。最近的证据表明，免疫功能障碍可能促成帕金森病的发展。在本研究中，我们发现，用α-突触核蛋白原纤维（PFFs）处理后，诱导多能干细胞（iPSC）衍生的人多巴胺能（DA）神经元会形成类似路易小体的包涵体，但只有在与免疫挑战模型（干扰素-γ或白细胞介素-1β处理）结合时，或与活化的小胶质细胞样细胞共培养时才会出现这种情况。暴露于干扰素-γ会损害多巴胺能神经元中的溶酶体功能，从而促成路易小体的形成。在给予PFF的同时敲低LAMP2或敲除GBA足以形成包涵体。最后，我们观察到iPSC衍生的多巴胺能神经元中的类似路易小体的包涵体是膜结合的，这表明它们不限于细胞质区室，可能是由于自噬功能障碍而形成的。总之，这些数据表明，免疫触发的溶酶体功能障碍可能促成帕金森病病理的发展。
