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α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells
Christian Hansen, … , Jia-Yi Li, Patrik Brundin
Christian Hansen, … , Jia-Yi Li, Patrik Brundin
Published January 18, 2011
Citation Information: J Clin Invest. 2011;121(2):715-725. https://doi.org/10.1172/JCI43366.
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Research Article Neuroscience Article has an altmetric score of 18

α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells

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Abstract

Post-mortem analyses of brains from patients with Parkinson disease who received fetal mesencephalic transplants show that α-synuclein–containing (α-syn–containing) Lewy bodies gradually appear in grafted neurons. Here, we explored whether intercellular transfer of α-syn from host to graft, followed by seeding of α-syn aggregation in recipient neurons, can contribute to this phenomenon. We assessed α-syn cell-to-cell transfer using microscopy, flow cytometry, and high-content screening in several coculture model systems. Coculturing cells engineered to express either GFP– or DsRed-tagged α-syn resulted in a gradual increase in double-labeled cells. Importantly, α-syn–GFP derived from 1 neuroblastoma cell line localized to red fluorescent aggregates in other cells expressing DsRed–α-syn, suggesting a seeding effect of transmitted α-syn. Extracellular α-syn was taken up by cells through endocytosis and interacted with intracellular α-syn. Next, following intracortical injection of recombinant α-syn in rats, we found neuronal uptake was attenuated by coinjection of an endocytosis inhibitor. Finally, we demonstrated in vivo transfer of α-syn between host cells and grafted dopaminergic neurons in mice overexpressing human α-syn. In summary, intercellularly transferred α-syn interacts with cytoplasmic α-syn and can propagate α-syn pathology. These results suggest that α-syn propagation is a key element in the progression of Parkinson disease pathology.

Authors

Christian Hansen, Elodie Angot, Ann-Louise Bergström, Jennifer A. Steiner, Laura Pieri, Gesine Paul, Tiago F. Outeiro, Ronald Melki, Pekka Kallunki, Karina Fog, Jia-Yi Li, Patrik Brundin

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Figure 3

Intercellular propagation of α-syn in SH-SY5Y cell culture.

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Intercellular propagation of α-syn in SH-SY5Y cell culture.
(A) Represen...
(A) Representative picture showing double-labeled SH-SY5Y cells after 14 days of coculture of stable SH-SY5Y cell lines expressing α-syn fused to either GFP or DsRed. Arrows represent transferred aggregates. (B) Confocal microscopy: representative pictures showing double-labeled SH-SY5Y cells after 14 days of coculture of stable SH-SY5Y cell lines expressing α-syn fused to either GFP or DsRed. Scale bars: 2 μM. (C) Upper panel: representative pictures showing double-labeled PC12 cells after 4 days of coculture of human SKMel5 and rat PC12/GFP cells. α-Syn was detected with a monoclonal antibody specific for human α-syn and an Alexa Fluor 568–coupled secondary antibody directed against mouse. Lower panel: comparative Western blot showing the expression level of α-syn in PC12 and SKMel5 cell lysates. Arrows represent double-labeled cells. (D) Representative pictures showing double-labeled N2A cells after 7 days of coculture of human SKMel5 and mouse N2A cells. α-Syn was detected with a monoclonal antibody specific for human α-syn and a Cy3-coupled secondary antibody directed against mouse, and N2A cells were probed with an antibody specific for MAP2 and an Alexa Fluor 488–coupled secondary antibody directed against rabbit. Arrows represent double-labeled cells. Original magnification, ×100 (A); ×40 (C); ×60 (D).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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