期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 121, 期 2, 页码 715-725出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI43366
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资金
- Swedish Research Council
- Human Frontier Science Program
- ERA-Net NEURON - MIPROTRAN
- Swedish Brain Foundation
- Parkinson Foundation (Sweden)
- Soderberg Foundation
- Michael J. Fox Foundation for Parkinson's Research
- Nordic Center of Excellence on Neurodegeneration
- Stiftelsen Lars Hiertas Minne
- Knut och Alice Wallenbergs stiftelse
- Sven Astell
- Centre National de la Recherche Scientifique
- Agence Nationale de la Recherche
Post-mortem analyses of brains from patients with Parkinson disease who received fetal mesencephalic transplants show that alpha-synuclein-containing (alpha-syn-containing) Lewy bodies gradually appear in grafted neurons. Here, we explored whether intercellular transfer of alpha-syn from host to graft, followed by seeding of alpha-syn aggregation in recipient neurons, can contribute to this phenomenon. We assessed alpha-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 alpha-syn resulted in a gradual increase in double-labeled cells. Importantly, alpha-syn-GFP derived from 1 neuroblastoma cell line localized to red fluorescent aggregates in other cells expressing DsRed-alpha-syn, suggesting a seeding effect of transmitted alpha-syn. Extracellular alpha-syn was taken up by cells through endocytosis and interacted with intracellular alpha-syn. Next, following intracortical injection of recombinant alpha-syn in rats, we found neuronal uptake was attenuated by coinjection of an endocytosis inhibitor. Finally, we demonstrated in vivo transfer of alpha-syn between host cells and grafted dopaminergic neurons in mice overexpressing human alpha-syn. In summary, intercellularly transferred alpha-syn interacts with cytoplasmic alpha-syn and can propagate alpha-syn pathology. These results suggest that alpha-syn propagation is a key element in the progression of Parkinson disease pathology.
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