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alpha-Synuclein pro...
alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells
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- Hansen, Christian (author)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Molekylär neurobiologi,Forskargrupper vid Lunds universitet,Department of Experimental Medical Science,Faculty of Medicine,Molecular Neurobiology,Lund University Research Groups
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- Angot, Elodie (author)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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Bergstrom, Ann-Louise (author)
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- Steiner, Jennifer (author)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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Pieri, Laura (author)
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- Paul-Visse, Gesine (author)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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Outeiro, Tiago F. (author)
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Melki, Ronald (author)
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Kallunki, Pekka (author)
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Fog, Karina (author)
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- Li, Jia-Yi (author)
- Lund University,Lunds universitet,Neural plasticitet och reparation,Forskargrupper vid Lunds universitet,Neural Plasticity and Repair,Lund University Research Groups
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- Brundin, Patrik (author)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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(creator_code:org_t)
- 2011
- 2011
- English.
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In: Journal of Clinical Investigation. - 0021-9738. ; 121:2, s. 715-725
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
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- By the author/editor
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Hansen, Christia ...
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Angot, Elodie
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Bergstrom, Ann-L ...
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Steiner, Jennife ...
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Pieri, Laura
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Paul-Visse, Gesi ...
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show more...
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Outeiro, Tiago F ...
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Melki, Ronald
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Kallunki, Pekka
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Fog, Karina
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Li, Jia-Yi
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Brundin, Patrik
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Journal of Clini ...
- By the university
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Lund University