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

Författare

  • Christian Hansen
  • Elodie Angot
  • Ann-Louise Bergstrom
  • Jennifer Steiner
  • Laura Pieri
  • Gesine Paul-Visse
  • Tiago F. Outeiro
  • Ronald Melki
  • Pekka Kallunki
  • Karina Fog
  • Jia-Yi Li
  • Patrik Brundin

Summary, in English

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.

Publiceringsår

2011

Språk

Engelska

Sidor

715-725

Publikation/Tidskrift/Serie

Journal of Clinical Investigation

Volym

121

Issue

2

Dokumenttyp

Artikel i tidskrift

Förlag

The American Society for Clinical Investigation

Ämne

  • Neurosciences

Status

Published

Forskningsgrupp

  • Molecular Neurobiology
  • Neural Plasticity and Repair

ISBN/ISSN/Övrigt

  • ISSN: 0021-9738