Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Autores
Villar Piqué, Anna; Da Fonseca, Tomás Lopes; Sant'Anna, Ricardo; Szegö, Éva Mónika; Fonseca Ornelas, Luis; Pinho, Raquel; Carija, Anita; Gerhardt, Ellen; Masaracchia, Caterina; Gonzalez, Enrique Abad; Rossetti, Giulia; Carloni, Paolo; Fernandez, Claudio Oscar; Foguel, Debora; Milosevic, Ira; Zweckstetter, Markus; Ventura, Salvador; Outeiro, Tiago Fleming
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.
Fil: Villar Piqué, Anna. Universität Göttingen; Alemania
Fil: Da Fonseca, Tomás Lopes. Universität Göttingen; Alemania
Fil: Sant'Anna, Ricardo. Universidade Federal do Rio de Janeiro; Brasil. Universitat Autònoma de Barcelona; España
Fil: Szegö, Éva Mónika. Universität Göttingen; Alemania
Fil: Fonseca Ornelas, Luis. Max-Planck-Institut für Biophysikalische Chemie; Alemania
Fil: Pinho, Raquel. Universität Göttingen; Alemania
Fil: Carija, Anita. Universitat Autònoma de Barcelona; España
Fil: Gerhardt, Ellen. Universität Göttingen; Alemania
Fil: Masaracchia, Caterina. Universität Göttingen; Alemania
Fil: Gonzalez, Enrique Abad. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania. Rwth Aachen University; Alemania
Fil: Rossetti, Giulia. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania. Aachen University; Alemania
Fil: Carloni, Paolo. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Universidad Nacional de Rosario; Argentina
Fil: Foguel, Debora. Universidade Federal do Rio de Janeiro; Brasil
Fil: Milosevic, Ira. European Neuroscience Institut; Alemania
Fil: Zweckstetter, Markus. Universität Göttingen; Alemania. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania. Max Planck Institute for Biophysical Chemistry; Alemania. German Centre for Degenerative Diseases; Alemania
Fil: Ventura, Salvador. Universitat Autònoma de Barcelona; España
Fil: Outeiro, Tiago Fleming. Universität Göttingen; Alemania. Max Planck Institute for Experimental Medicine Göttingen; Alemania
Materia
COPPER
PROTEIN AGGREGATION
INCLUSIONS
α-SYNUCLEIN
H50Q MUTATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/111370
Acceder
id CONICETDig_8f480781dba902ff18aa3f7eb31023d5
oai_identifier_str oai:ri.conicet.gov.ar:11336/111370
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicityVillar Piqué, AnnaDa Fonseca, Tomás LopesSant'Anna, RicardoSzegö, Éva MónikaFonseca Ornelas, LuisPinho, RaquelCarija, AnitaGerhardt, EllenMasaracchia, CaterinaGonzalez, Enrique AbadRossetti, GiuliaCarloni, PaoloFernandez, Claudio OscarFoguel, DeboraMilosevic, IraZweckstetter, MarkusVentura, SalvadorOuteiro, Tiago FlemingCOPPERPROTEIN AGGREGATIONINCLUSIONSα-SYNUCLEINH50Q MUTATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.Fil: Villar Piqué, Anna. Universität Göttingen; AlemaniaFil: Da Fonseca, Tomás Lopes. Universität Göttingen; AlemaniaFil: Sant'Anna, Ricardo. Universidade Federal do Rio de Janeiro; Brasil. Universitat Autònoma de Barcelona; EspañaFil: Szegö, Éva Mónika. Universität Göttingen; AlemaniaFil: Fonseca Ornelas, Luis. Max-Planck-Institut für Biophysikalische Chemie; AlemaniaFil: Pinho, Raquel. Universität Göttingen; AlemaniaFil: Carija, Anita. Universitat Autònoma de Barcelona; EspañaFil: Gerhardt, Ellen. Universität Göttingen; AlemaniaFil: Masaracchia, Caterina. Universität Göttingen; AlemaniaFil: Gonzalez, Enrique Abad. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania. Rwth Aachen University; AlemaniaFil: Rossetti, Giulia. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania. Aachen University; AlemaniaFil: Carloni, Paolo. Helmholtz Gemeinschaft. Forschungszentrum Jülich; AlemaniaFil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Universidad Nacional de Rosario; ArgentinaFil: Foguel, Debora. Universidade Federal do Rio de Janeiro; BrasilFil: Milosevic, Ira. European Neuroscience Institut; AlemaniaFil: Zweckstetter, Markus. Universität Göttingen; Alemania. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania. Max Planck Institute for Biophysical Chemistry; Alemania. German Centre for Degenerative Diseases; AlemaniaFil: Ventura, Salvador. Universitat Autònoma de Barcelona; EspañaFil: Outeiro, Tiago Fleming. Universität Göttingen; Alemania. Max Planck Institute for Experimental Medicine Göttingen; AlemaniaNational Academy of Sciences2016-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/111370Villar Piqué, Anna; Da Fonseca, Tomás Lopes; Sant'Anna, Ricardo; Szegö, Éva Mónika; Fonseca Ornelas, Luis; et al.; Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 113; 42; 10-2016; 6506-65150027-84241091-6490CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1606791113info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/113/42/E6506info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:01:33Zoai:ri.conicet.gov.ar:11336/111370instacron: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 10:01:33.786CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
title Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
spellingShingle Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
Villar Piqué, Anna
COPPER
PROTEIN AGGREGATION
INCLUSIONS
α-SYNUCLEIN
H50Q MUTATION
title_short Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
title_full Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
title_fullStr Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
title_full_unstemmed Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
title_sort Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
dc.creator.none.fl_str_mv Villar Piqué, Anna
Da Fonseca, Tomás Lopes
Sant'Anna, Ricardo
Szegö, Éva Mónika
Fonseca Ornelas, Luis
Pinho, Raquel
Carija, Anita
Gerhardt, Ellen
Masaracchia, Caterina
Gonzalez, Enrique Abad
Rossetti, Giulia
Carloni, Paolo
Fernandez, Claudio Oscar
Foguel, Debora
Milosevic, Ira
Zweckstetter, Markus
Ventura, Salvador
Outeiro, Tiago Fleming
author Villar Piqué, Anna
author_facet Villar Piqué, Anna
Da Fonseca, Tomás Lopes
Sant'Anna, Ricardo
Szegö, Éva Mónika
Fonseca Ornelas, Luis
Pinho, Raquel
Carija, Anita
Gerhardt, Ellen
Masaracchia, Caterina
Gonzalez, Enrique Abad
Rossetti, Giulia
Carloni, Paolo
Fernandez, Claudio Oscar
Foguel, Debora
Milosevic, Ira
Zweckstetter, Markus
Ventura, Salvador
Outeiro, Tiago Fleming
author_role author
author2 Da Fonseca, Tomás Lopes
Sant'Anna, Ricardo
Szegö, Éva Mónika
Fonseca Ornelas, Luis
Pinho, Raquel
Carija, Anita
Gerhardt, Ellen
Masaracchia, Caterina
Gonzalez, Enrique Abad
Rossetti, Giulia
Carloni, Paolo
Fernandez, Claudio Oscar
Foguel, Debora
Milosevic, Ira
Zweckstetter, Markus
Ventura, Salvador
Outeiro, Tiago Fleming
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv COPPER
PROTEIN AGGREGATION
INCLUSIONS
α-SYNUCLEIN
H50Q MUTATION
topic COPPER
PROTEIN AGGREGATION
INCLUSIONS
α-SYNUCLEIN
H50Q MUTATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.
Fil: Villar Piqué, Anna. Universität Göttingen; Alemania
Fil: Da Fonseca, Tomás Lopes. Universität Göttingen; Alemania
Fil: Sant'Anna, Ricardo. Universidade Federal do Rio de Janeiro; Brasil. Universitat Autònoma de Barcelona; España
Fil: Szegö, Éva Mónika. Universität Göttingen; Alemania
Fil: Fonseca Ornelas, Luis. Max-Planck-Institut für Biophysikalische Chemie; Alemania
Fil: Pinho, Raquel. Universität Göttingen; Alemania
Fil: Carija, Anita. Universitat Autònoma de Barcelona; España
Fil: Gerhardt, Ellen. Universität Göttingen; Alemania
Fil: Masaracchia, Caterina. Universität Göttingen; Alemania
Fil: Gonzalez, Enrique Abad. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania. Rwth Aachen University; Alemania
Fil: Rossetti, Giulia. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania. Aachen University; Alemania
Fil: Carloni, Paolo. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania
Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Universidad Nacional de Rosario; Argentina
Fil: Foguel, Debora. Universidade Federal do Rio de Janeiro; Brasil
Fil: Milosevic, Ira. European Neuroscience Institut; Alemania
Fil: Zweckstetter, Markus. Universität Göttingen; Alemania. Helmholtz Gemeinschaft. Forschungszentrum Jülich; Alemania. Max Planck Institute for Biophysical Chemistry; Alemania. German Centre for Degenerative Diseases; Alemania
Fil: Ventura, Salvador. Universitat Autònoma de Barcelona; España
Fil: Outeiro, Tiago Fleming. Universität Göttingen; Alemania. Max Planck Institute for Experimental Medicine Göttingen; Alemania
description Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.
publishDate 2016
dc.date.none.fl_str_mv 2016-10
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/11336/111370
Villar Piqué, Anna; Da Fonseca, Tomás Lopes; Sant'Anna, Ricardo; Szegö, Éva Mónika; Fonseca Ornelas, Luis; et al.; Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 113; 42; 10-2016; 6506-6515
0027-8424
1091-6490
CONICET Digital
CONICET
url http://hdl.handle.net/11336/111370
identifier_str_mv Villar Piqué, Anna; Da Fonseca, Tomás Lopes; Sant'Anna, Ricardo; Szegö, Éva Mónika; Fonseca Ornelas, Luis; et al.; Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 113; 42; 10-2016; 6506-6515
0027-8424
1091-6490
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1606791113
info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/113/42/E6506
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
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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score 13.13397

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