加拿大麦吉尔大学Peter S. McPherso团队，通过连续暴露于α-突触核蛋白原纤维和促炎细胞因子，模拟人类多巴胺能神经元帕金森病病理。该研究于2024年10月8日发表于国际一流学术期刊《自然—神经科学》杂志上。

据悉，路易小体(lewis bodies, LBs)是富含α-突触核蛋白的细胞内内含物，是帕金森病(PD)病理的标志，但LB形成的细胞模型尚不清楚。最近的证据表明，免疫功能障碍可能有助于PD的发展。

在这项研究中，研究团队发现诱导多能干细胞(iPSC)来源的人多巴胺能(DA)神经元，在α-突触核蛋白预形成原纤维(PFFs)处理后形成路易小体(lewis bodies, LBs)样细胞，但只有在与免疫刺激模型(干扰素-γ或白细胞介素-1β处理)偶联，或与活化的小胶质样细胞共培养时才会形成LB样细胞。

暴露于干扰素-γ损害DA神经元的溶酶体功能，促进LB的形成。LAMP2的敲除或GBA的敲除与PFF联合使用足以形成内含物。最后，研究人员观察到iPSC来源的DA神经元中的LB样嵌合体是膜结合的，这表明它们不仅局限于细胞质室，而且可能是由于自噬功能障碍而形成的。综上所述，这些数据表明免疫触发的溶酶体功能障碍可能有助于PD病理的发展。

附：英文原文

Title: Modeling Parkinson’s disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines

Author: 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, Sgula, 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.

Issue&Volume: 2024-10-08

Abstract: 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.

DOI: 10.1038/s41593-024-01775-4

Source: https://www.nature.com/articles/s41593-024-01775-4