Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease

Autores
Prymaczok, Natalia Cecilia; de Francesco, Pablo Nicolás; Mazzetti, Samanta; Humbert Claude, Marie; Tenenbaum, Liliane; Cappelletti, Graziella; Masliah, Eliezer; Perello, Mario; Riek, Roland; Gerez, Juan Atilio
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Parkinson´s disease is characterized by a progressive accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies in the nervous system. Lewy bodies can arise from the cell-to-cell propagation of αSyn, which can occur via sequential steps of secretion and uptake. Here, by fusing a removable short signal peptide to the N-terminus of αSyn, we developed a novel mouse model with enhanced αSyn secretion and cell-to-cell transmission. Expression of the secreted αSyn in the mouse brain was under the control of a novel hybrid promoter in combination with adeno-associated virus serotype 9 (AAV9). This combination of promoter and viral vector induced a robust expression in neurons but not in the glia of injected mice. Biochemical characterization of the secreted αSyn revealed that, in cultured cells, this protein is released to the extracellular milieu via conventional secretion. The released αSyn is then internalized and processed by acceptor cells via the endosome-lysosome pathway indicating that the secreted αSyn is cell-to-cell transmitted. The secreted αSyn is aggregation-prone and amyloidogenic, and when expressed in the brain of wild-type non-transgenic mice, it induces a Parkinson´s disease-like phenotype that includes a robust αSyn pathology in the substantia nigra, neuronal loss, neuroinflammation, and motor deficits, all the key features of experimental animal models of Parkinson´s disease. In summary, a novel animal model of Parkinson´s disease based on enhanced cell-to-cell transmission of αSyn was developed. The neuron-produced cell-to-cell transmitted αSyn triggers all phenotypic features of experimental Parkinson´s disease in mice.
Fil: Prymaczok, Natalia Cecilia. Institute Of Molecular Physical Science; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: de Francesco, Pablo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Mazzetti, Samanta. Università degli Studi di Milano; Italia
Fil: Humbert Claude, Marie. Universite de Lausanne; Suiza
Fil: Tenenbaum, Liliane. Universite de Lausanne; Suiza
Fil: Cappelletti, Graziella. Università degli Studi di Milano; Italia
Fil: Masliah, Eliezer. No especifíca;
Fil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Riek, Roland. Institute Of Molecular Physical Science; Suiza
Fil: Gerez, Juan Atilio. Institute Of Molecular Physical Science; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
ALPHA-SYNUCLEIN
PARKINSONS
ALPHA-SYNUCLEIN SECRETION
CELL-TO-CELL TRANSMISION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/262941
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/262941
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s diseasePrymaczok, Natalia Ceciliade Francesco, Pablo NicolásMazzetti, SamantaHumbert Claude, MarieTenenbaum, LilianeCappelletti, GraziellaMasliah, EliezerPerello, MarioRiek, RolandGerez, Juan AtilioALPHA-SYNUCLEINPARKINSONSALPHA-SYNUCLEIN SECRETIONCELL-TO-CELL TRANSMISIONhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Parkinson´s disease is characterized by a progressive accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies in the nervous system. Lewy bodies can arise from the cell-to-cell propagation of αSyn, which can occur via sequential steps of secretion and uptake. Here, by fusing a removable short signal peptide to the N-terminus of αSyn, we developed a novel mouse model with enhanced αSyn secretion and cell-to-cell transmission. Expression of the secreted αSyn in the mouse brain was under the control of a novel hybrid promoter in combination with adeno-associated virus serotype 9 (AAV9). This combination of promoter and viral vector induced a robust expression in neurons but not in the glia of injected mice. Biochemical characterization of the secreted αSyn revealed that, in cultured cells, this protein is released to the extracellular milieu via conventional secretion. The released αSyn is then internalized and processed by acceptor cells via the endosome-lysosome pathway indicating that the secreted αSyn is cell-to-cell transmitted. The secreted αSyn is aggregation-prone and amyloidogenic, and when expressed in the brain of wild-type non-transgenic mice, it induces a Parkinson´s disease-like phenotype that includes a robust αSyn pathology in the substantia nigra, neuronal loss, neuroinflammation, and motor deficits, all the key features of experimental animal models of Parkinson´s disease. In summary, a novel animal model of Parkinson´s disease based on enhanced cell-to-cell transmission of αSyn was developed. The neuron-produced cell-to-cell transmitted αSyn triggers all phenotypic features of experimental Parkinson´s disease in mice.Fil: Prymaczok, Natalia Cecilia. Institute Of Molecular Physical Science; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: de Francesco, Pablo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Mazzetti, Samanta. Università degli Studi di Milano; ItaliaFil: Humbert Claude, Marie. Universite de Lausanne; SuizaFil: Tenenbaum, Liliane. Universite de Lausanne; SuizaFil: Cappelletti, Graziella. Università degli Studi di Milano; ItaliaFil: Masliah, Eliezer. No especifíca;Fil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Riek, Roland. Institute Of Molecular Physical Science; SuizaFil: Gerez, Juan Atilio. Institute Of Molecular Physical Science; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaNature2024-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/262941Prymaczok, Natalia Cecilia; de Francesco, Pablo Nicolás; Mazzetti, Samanta; Humbert Claude, Marie; Tenenbaum, Liliane; et al.; Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease; Nature; npj Parkinson's Disease; 10; 1; 1-2024; 1-182373-8057CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41531-023-00618-6info:eu-repo/semantics/altIdentifier/doi/10.1038/s41531-023-00618-6info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:05:54Zoai:ri.conicet.gov.ar:11336/262941instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:05:54.91CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease
title Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease
spellingShingle Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease
Prymaczok, Natalia Cecilia
ALPHA-SYNUCLEIN
PARKINSONS
ALPHA-SYNUCLEIN SECRETION
CELL-TO-CELL TRANSMISION
title_short Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease
title_full Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease
title_fullStr Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease
title_full_unstemmed Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease
title_sort Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease
dc.creator.none.fl_str_mv Prymaczok, Natalia Cecilia
de Francesco, Pablo Nicolás
Mazzetti, Samanta
Humbert Claude, Marie
Tenenbaum, Liliane
Cappelletti, Graziella
Masliah, Eliezer
Perello, Mario
Riek, Roland
Gerez, Juan Atilio
author Prymaczok, Natalia Cecilia
author_facet Prymaczok, Natalia Cecilia
de Francesco, Pablo Nicolás
Mazzetti, Samanta
Humbert Claude, Marie
Tenenbaum, Liliane
Cappelletti, Graziella
Masliah, Eliezer
Perello, Mario
Riek, Roland
Gerez, Juan Atilio
author_role author
author2 de Francesco, Pablo Nicolás
Mazzetti, Samanta
Humbert Claude, Marie
Tenenbaum, Liliane
Cappelletti, Graziella
Masliah, Eliezer
Perello, Mario
Riek, Roland
Gerez, Juan Atilio
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ALPHA-SYNUCLEIN
PARKINSONS
ALPHA-SYNUCLEIN SECRETION
CELL-TO-CELL TRANSMISION
topic ALPHA-SYNUCLEIN
PARKINSONS
ALPHA-SYNUCLEIN SECRETION
CELL-TO-CELL TRANSMISION
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Parkinson´s disease is characterized by a progressive accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies in the nervous system. Lewy bodies can arise from the cell-to-cell propagation of αSyn, which can occur via sequential steps of secretion and uptake. Here, by fusing a removable short signal peptide to the N-terminus of αSyn, we developed a novel mouse model with enhanced αSyn secretion and cell-to-cell transmission. Expression of the secreted αSyn in the mouse brain was under the control of a novel hybrid promoter in combination with adeno-associated virus serotype 9 (AAV9). This combination of promoter and viral vector induced a robust expression in neurons but not in the glia of injected mice. Biochemical characterization of the secreted αSyn revealed that, in cultured cells, this protein is released to the extracellular milieu via conventional secretion. The released αSyn is then internalized and processed by acceptor cells via the endosome-lysosome pathway indicating that the secreted αSyn is cell-to-cell transmitted. The secreted αSyn is aggregation-prone and amyloidogenic, and when expressed in the brain of wild-type non-transgenic mice, it induces a Parkinson´s disease-like phenotype that includes a robust αSyn pathology in the substantia nigra, neuronal loss, neuroinflammation, and motor deficits, all the key features of experimental animal models of Parkinson´s disease. In summary, a novel animal model of Parkinson´s disease based on enhanced cell-to-cell transmission of αSyn was developed. The neuron-produced cell-to-cell transmitted αSyn triggers all phenotypic features of experimental Parkinson´s disease in mice.
Fil: Prymaczok, Natalia Cecilia. Institute Of Molecular Physical Science; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: de Francesco, Pablo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Mazzetti, Samanta. Università degli Studi di Milano; Italia
Fil: Humbert Claude, Marie. Universite de Lausanne; Suiza
Fil: Tenenbaum, Liliane. Universite de Lausanne; Suiza
Fil: Cappelletti, Graziella. Università degli Studi di Milano; Italia
Fil: Masliah, Eliezer. No especifíca;
Fil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Riek, Roland. Institute Of Molecular Physical Science; Suiza
Fil: Gerez, Juan Atilio. Institute Of Molecular Physical Science; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Parkinson´s disease is characterized by a progressive accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies in the nervous system. Lewy bodies can arise from the cell-to-cell propagation of αSyn, which can occur via sequential steps of secretion and uptake. Here, by fusing a removable short signal peptide to the N-terminus of αSyn, we developed a novel mouse model with enhanced αSyn secretion and cell-to-cell transmission. Expression of the secreted αSyn in the mouse brain was under the control of a novel hybrid promoter in combination with adeno-associated virus serotype 9 (AAV9). This combination of promoter and viral vector induced a robust expression in neurons but not in the glia of injected mice. Biochemical characterization of the secreted αSyn revealed that, in cultured cells, this protein is released to the extracellular milieu via conventional secretion. The released αSyn is then internalized and processed by acceptor cells via the endosome-lysosome pathway indicating that the secreted αSyn is cell-to-cell transmitted. The secreted αSyn is aggregation-prone and amyloidogenic, and when expressed in the brain of wild-type non-transgenic mice, it induces a Parkinson´s disease-like phenotype that includes a robust αSyn pathology in the substantia nigra, neuronal loss, neuroinflammation, and motor deficits, all the key features of experimental animal models of Parkinson´s disease. In summary, a novel animal model of Parkinson´s disease based on enhanced cell-to-cell transmission of αSyn was developed. The neuron-produced cell-to-cell transmitted αSyn triggers all phenotypic features of experimental Parkinson´s disease in mice.
publishDate 2024
dc.date.none.fl_str_mv 2024-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/262941
Prymaczok, Natalia Cecilia; de Francesco, Pablo Nicolás; Mazzetti, Samanta; Humbert Claude, Marie; Tenenbaum, Liliane; et al.; Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease; Nature; npj Parkinson's Disease; 10; 1; 1-2024; 1-18
2373-8057
CONICET Digital
CONICET
url http://hdl.handle.net/11336/262941
identifier_str_mv Prymaczok, Natalia Cecilia; de Francesco, Pablo Nicolás; Mazzetti, Samanta; Humbert Claude, Marie; Tenenbaum, Liliane; et al.; Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease; Nature; npj Parkinson's Disease; 10; 1; 1-2024; 1-18
2373-8057
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41531-023-00618-6
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41531-023-00618-6
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature
publisher.none.fl_str_mv Nature
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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