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

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

Publikation: Bidrag til tidsskriftTidsskriftsartikelForskningpeer review

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.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Investigation
Vol/bind121
Udgave nummer2
Sider (fra-til)715-725
Antal sider11
ISSN0021-9738
DOI
StatusUdgivet - 1 feb. 2011
Udgivet eksterntJa

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