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

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

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Abstract

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.
Original languageEnglish
Pages (from-to)715-725
JournalJournal of Clinical Investigation
Volume121
Issue number2
DOIs
Publication statusPublished - 2011

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Neuronal Survival (013212041), Neural Plasticity and Repair (013210080)

Subject classification (UKÄ)

  • Neurosciences

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