Armin Bayati, Riham Ayoubi, Adriana Aguila, Cornelia E. Zorca, Ghislaine Deyab, Chanshuai Han, Sherilyn Junelle Recinto, Emmanuelle Nguyen-Renou, Cecilia Rocha, Gilles Maussion, Wen Luo, Irina Shlaifer, Emily Banks, Ian McDowell, Esther Del Cid Pellitero, Xue Er Ding, Behrang Sharif, Philippe Séguéla, Moein Yaqubi, Carol X.-Q. Chen, Zhipeng You, Narges Abdian, Heidi M. McBride, Edward A. Fon, Jo Anne Stratton, Thomas M. Durcan, Patrick C. Nahirney, Peter S. McPherson
{"title":"Modeling Parkinson’s disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines","authors":"Armin Bayati, Riham Ayoubi, Adriana Aguila, Cornelia E. Zorca, Ghislaine Deyab, Chanshuai Han, Sherilyn Junelle Recinto, Emmanuelle Nguyen-Renou, Cecilia Rocha, Gilles Maussion, Wen Luo, Irina Shlaifer, Emily Banks, Ian McDowell, Esther Del Cid Pellitero, Xue Er Ding, Behrang Sharif, Philippe Séguéla, Moein Yaqubi, Carol X.-Q. Chen, Zhipeng You, Narges Abdian, Heidi M. McBride, Edward A. Fon, Jo Anne Stratton, Thomas M. Durcan, Patrick C. Nahirney, Peter S. McPherson","doi":"10.1038/s41593-024-01775-4","DOIUrl":null,"url":null,"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. Bayati et al. discovered that sequential treatment of iPSC-derived dopaminergic neurons with α-synuclein fibrils and proinflammatory cytokines leads to the formation of Lewy body–like inclusions, through the downregulation of lysosomal proteins.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 12","pages":"2401-2416"},"PeriodicalIF":21.2000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature neuroscience","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41593-024-01775-4","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
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. Bayati et al. discovered that sequential treatment of iPSC-derived dopaminergic neurons with α-synuclein fibrils and proinflammatory cytokines leads to the formation of Lewy body–like inclusions, through the downregulation of lysosomal proteins.
期刊介绍:
Nature Neuroscience, a multidisciplinary journal, publishes papers of the utmost quality and significance across all realms of neuroscience. The editors welcome contributions spanning molecular, cellular, systems, and cognitive neuroscience, along with psychophysics, computational modeling, and nervous system disorders. While no area is off-limits, studies offering fundamental insights into nervous system function receive priority.
The journal offers high visibility to both readers and authors, fostering interdisciplinary communication and accessibility to a broad audience. It maintains high standards of copy editing and production, rigorous peer review, rapid publication, and operates independently from academic societies and other vested interests.
In addition to primary research, Nature Neuroscience features news and views, reviews, editorials, commentaries, perspectives, book reviews, and correspondence, aiming to serve as the voice of the global neuroscience community.