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

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

SUBMITTER: Hansen C 

PROVIDER: S-EPMC3026723 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature