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

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
Angot, Elodie (author)
Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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
Pieri, Laura (author)
Paul-Visse, Gesine (author)
Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
Outeiro, Tiago F. (author)
Melki, Ronald (author)
Kallunki, Pekka (author)
Fog, Karina (author)
Li, Jia-Yi (author)
Lund University,Lunds universitet,Neural plasticitet och reparation,Forskargrupper vid Lunds universitet,Neural Plasticity and Repair,Lund University Research Groups
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.
In: Journal of Clinical Investigation. - 0021-9738. ; 121:2, s. 715-725
  • Journal article (peer-reviewed)
Abstract Subject headings
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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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