Document Detail


α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells.
MedLine Citation:
PMID:  21245577     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-01-18
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  121     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-02-02     Completed Date:  2011-03-28     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  715-25     Citation Subset:  AIM; IM    
Affiliation:
Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain / metabolism*
Cell Transplantation*
Cells, Cultured
Coculture Techniques
Culture Media, Conditioned
Dopamine / metabolism*
HEK293 Cells
Humans
Lewy Bodies / metabolism
Mice
Neurons / cytology,  metabolism*
Parkinson Disease / metabolism,  pathology
Rats
Recombinant Fusion Proteins / genetics,  metabolism
alpha-Synuclein / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Culture Media, Conditioned; 0/Recombinant Fusion Proteins; 0/alpha-Synuclein
Comments/Corrections

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