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.
Highlights
The neuropathological hallmarks of Parkinson disease (PD), Lewy bodies (LB) and Lewy neurites (LN), are intracytoplasmic inclusions that develop in the cell body and neurites of affected neurons, respectively. α-Synuclein (α-syn), the primary component of these proteinaceous aggregates [1], is found in most cellular compartments, but enriched in presynaptic terminals [2]. α-Syn has been suggested to play a role in vesicular transport and neuro transmitter release [3] and to contribute to SNARE complex formation at the presynaptic terminals via a nonclassical chaperone activity [4]
We provide what we believe is the first evidence for a seeding activity of propagated α-syn subsequent to its cell-to-cell transfer in cell coculture system
Using confocal microscopy, we found a fraction of imported α-syn–GFP nuclei to be enveloped by α-syn–DsRed derived from the recipient cell
Summary
The neuropathological hallmarks of Parkinson disease (PD), Lewy bodies (LB) and Lewy neurites (LN), are intracytoplasmic inclusions that develop in the cell body and neurites of affected neurons, respectively. α-Synuclein (α-syn), the primary component of these proteinaceous aggregates [1], is found in most cellular compartments, but enriched in presynaptic terminals [2]. α-Syn has been suggested to play a role in vesicular transport and neuro transmitter release [3] and to contribute to SNARE complex formation at the presynaptic terminals via a nonclassical chaperone activity [4]. Α-syn–positive LB and LN were detected in grafted neurons in PD patients who received transplants of embryonic mesencephalic tissue more than a decade prior to their deaths [10,11,12]. These clinical observations are consistent with the Braak hypothesis; a neurotropic pathogen may cause the spread of LB and LN pathology from a peripheral origin (olfactory bulb, intestine) to the brainstem and to more widespread cerebral areas during PD progression [13]. Jia-Yi Li and Patrik Brundin are co–senior authors
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