α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells
Identifieur interne : 001511 ( Main/Exploration ); précédent : 001510; suivant : 001512α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells
Auteurs : Christian Hansen [Suède] ; Elodie Angot [Suède] ; Ann-Louise Bergström [Danemark] ; Jennifer A. Steiner [Suède] ; Laura Pieri [France] ; Gesine Paul [Suède] ; Tiago F. Outeiro [Portugal] ; Ronald Melki [France] ; Pekka Kallunki [Danemark] ; Karina Fog [Danemark] ; Jia-Yi Li [Suède] ; Patrik Brundin [Suède]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2011.
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.
Url:
DOI: 10.1172/JCI43366
PubMed: 21245577
PubMed Central: 3026723
Affiliations:
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Lundbeck A/S, Valby, Denmark.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Danemark</country><wicri:regionArea>H. Lundbeck A/S, Valby</wicri:regionArea><wicri:noRegion>Valby</wicri:noRegion></affiliation></author><author><name sortKey="Steiner, Jennifer A" sort="Steiner, Jennifer A" uniqKey="Steiner J" first="Jennifer A." last="Steiner">Jennifer A. Steiner</name><affiliation wicri:level="1"><nlm:aff id="JCI43366">Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Pieri, Laura" sort="Pieri, Laura" uniqKey="Pieri L" first="Laura" last="Pieri">Laura Pieri</name><affiliation wicri:level="3"><nlm:aff id="JCI43366">Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Gif-sur-Yvette, France.</nlm:aff><country xml:lang="fr" wicri:curation="lc">France</country><wicri:regionArea>Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Gif-sur-Yvette</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Gif-sur-Yvette</settlement></placeName></affiliation></author><author><name sortKey="Paul, Gesine" sort="Paul, Gesine" uniqKey="Paul G" first="Gesine" last="Paul">Gesine Paul</name><affiliation wicri:level="1"><nlm:aff id="JCI43366">Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Outeiro, Tiago F" sort="Outeiro, Tiago F" uniqKey="Outeiro T" first="Tiago F." last="Outeiro">Tiago F. Outeiro</name><affiliation wicri:level="1"><nlm:aff id="JCI43366">Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisbon, Portugal.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Portugal</country><wicri:regionArea>Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisbon</wicri:regionArea><wicri:noRegion>Lisbon</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="JCI43366">Instituto de Fisiologia, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisbon, Portugal.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Portugal</country><wicri:regionArea>Instituto de Fisiologia, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisbon</wicri:regionArea><wicri:noRegion>Lisbon</wicri:noRegion></affiliation></author><author><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name><affiliation wicri:level="3"><nlm:aff id="JCI43366">Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Gif-sur-Yvette, France.</nlm:aff><country xml:lang="fr" wicri:curation="lc">France</country><wicri:regionArea>Laboratoire d’Enzymologie et Biochimie Structurales, CNRS, Gif-sur-Yvette</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Gif-sur-Yvette</settlement></placeName></affiliation></author><author><name sortKey="Kallunki, Pekka" sort="Kallunki, Pekka" uniqKey="Kallunki P" first="Pekka" last="Kallunki">Pekka Kallunki</name><affiliation wicri:level="1"><nlm:aff id="JCI43366">H. Lundbeck A/S, Valby, Denmark.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Danemark</country><wicri:regionArea>H. Lundbeck A/S, Valby</wicri:regionArea><wicri:noRegion>Valby</wicri:noRegion></affiliation></author><author><name sortKey="Fog, Karina" sort="Fog, Karina" uniqKey="Fog K" first="Karina" last="Fog">Karina Fog</name><affiliation wicri:level="1"><nlm:aff id="JCI43366">H. Lundbeck A/S, Valby, Denmark.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Danemark</country><wicri:regionArea>H. Lundbeck A/S, Valby</wicri:regionArea><wicri:noRegion>Valby</wicri:noRegion></affiliation></author><author><name sortKey="Li, Jia Yi" sort="Li, Jia Yi" uniqKey="Li J" first="Jia-Yi" last="Li">Jia-Yi Li</name><affiliation wicri:level="1"><nlm:aff id="JCI43366">Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Brundin, Patrik" sort="Brundin, Patrik" uniqKey="Brundin P" first="Patrik" last="Brundin">Patrik Brundin</name><affiliation wicri:level="1"><nlm:aff id="JCI43366">Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><idno type="eISSN">1558-8238</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front></TEI><affiliations><list><country><li>Danemark</li><li>France</li><li>Portugal</li><li>Suède</li></country><region><li>Île-de-France</li></region><settlement><li>Gif-sur-Yvette</li></settlement></list><tree><country name="Suède"><noRegion><name sortKey="Hansen, Christian" sort="Hansen, Christian" uniqKey="Hansen C" first="Christian" last="Hansen">Christian Hansen</name></noRegion><name sortKey="Angot, Elodie" sort="Angot, Elodie" uniqKey="Angot E" first="Elodie" last="Angot">Elodie Angot</name><name sortKey="Brundin, Patrik" sort="Brundin, Patrik" uniqKey="Brundin P" first="Patrik" last="Brundin">Patrik Brundin</name><name sortKey="Li, Jia Yi" sort="Li, Jia Yi" uniqKey="Li J" first="Jia-Yi" last="Li">Jia-Yi Li</name><name sortKey="Paul, Gesine" sort="Paul, Gesine" uniqKey="Paul G" first="Gesine" last="Paul">Gesine Paul</name><name sortKey="Steiner, Jennifer A" sort="Steiner, Jennifer A" uniqKey="Steiner J" first="Jennifer A." last="Steiner">Jennifer A. Steiner</name></country><country name="Danemark"><noRegion><name sortKey="Bergstrom, Ann Louise" sort="Bergstrom, Ann Louise" uniqKey="Bergstrom A" first="Ann-Louise" last="Bergström">Ann-Louise Bergström</name></noRegion><name sortKey="Fog, Karina" sort="Fog, Karina" uniqKey="Fog K" first="Karina" last="Fog">Karina Fog</name><name sortKey="Kallunki, Pekka" sort="Kallunki, Pekka" uniqKey="Kallunki P" first="Pekka" last="Kallunki">Pekka Kallunki</name></country><country name="France"><region name="Île-de-France"><name sortKey="Pieri, Laura" sort="Pieri, Laura" uniqKey="Pieri L" first="Laura" last="Pieri">Laura Pieri</name></region><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name></country><country name="Portugal"><noRegion><name sortKey="Outeiro, Tiago F" sort="Outeiro, Tiago F" uniqKey="Outeiro T" first="Tiago F." last="Outeiro">Tiago F. Outeiro</name></noRegion><name sortKey="Outeiro, Tiago F" sort="Outeiro, Tiago F" uniqKey="Outeiro T" first="Tiago F." last="Outeiro">Tiago F. Outeiro</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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