Cited by 842Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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

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Hansen, Christian, Angot, Elodie, Bergström, Ann-Louise, Steiner, Jennifer A., Pieri, Laura, Paul, Gesine, Outeiro, Tiago F., Melki, Ronald +4 more·2011·Journal of Clinical Investigation

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.

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Authors
Hansen, C., Angot, E., Bergström, A.-L., Steiner, J. A., Pieri, L., Paul, G., Outeiro, T. F., Melki, R., Kallunki, P., Fog, K., Li, J.-Y., & Brundin, P.
Affiliations
  • Lund University (SE)
  • Lundbeck (Denmark) (DK)
  • Laboratoire d'Enzymologie et Biochimie Structurales (FR)
  • University of Lisbon (PT)
Corresponding author
Brundin, Patrik
Venue
Journal of Clinical Investigation
Published
2011-02-01
Volume
121
Issue
2
Pages
715-725
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2046885195
Cited by
842
References
42
Citations by year
2026: 13 · 2025: 26 · 2024: 25 · 2023: 31 · 2022: 43 · 2021: 69 · 2020: 70 · 2019: 59 · 2018: 51 · 2017: 72 · 2016: 68 · 2015: 68 · 2014: 64 · 2013: 77 · 2012: 64
FWCI
50.08
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • Lund University Publications (Lund University) (submittedVersion, other-oa)
Funders
  • Michael J. Fox Foundation for Parkinson's Research
  • Agence Nationale de la Recherche
  • Knut och Alice Wallenbergs Stiftelse
  • Vetenskapsrådet
  • Stiftelsen Lars Hiertas Minne
  • Centre National de la Recherche Scientifique
  • Parkinsonfonden
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
alpha-synuclein, Parkinson's disease, Lewy bodies, intercellular transfer, endocytosis, neuroblastoma cells, intracortical injection
MeSH terms
Animals, Brain, Cells, Cultured, Dopamine, Humans, Neurons, Parkinson Disease, Recombinant Fusion Proteins, Lewy Bodies, Culture Media, Conditioned, Cell Transplantation, Coculture Techniques, Mice, Rats, alpha-Synuclein, HEK293 Cells

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