α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells.
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.
Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
Christian
C
Hansen
Elodie
E
Angot
Ann-Louise
AL
Bergström
Jennifer A
JA
Steiner
Laura
L
Pieri
Gesine
G
Paul
Tiago F
TF
Outeiro
Ronald
R
Melki
Pekka
P
Kallunki
Karina
K
Fog
Jia-Yi
JY
Li
Patrik
P
Brundin
D000818:Animals; D001921:Brain / Q000378:metabolism*; D017690:Cell Transplantation; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004298:Dopamine / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D017077:Culture Media, Conditioned; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; D004298:Dopamine
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