Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity

Autores
Avila, Cesar Luis; Torres Bugeau, Clarisa Maria; Barbosa, Leandro R. S.; Morandé Sales, Elisa; Ouidja, Mohand O.; Socias, Sergio Benjamin; Celej, Maria Soledad; Raisman Vozari, Rita; Papy Garcia, Dulce; Itri, Rosangela; Chehin, Rosana Nieves
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme that has been associated with neurodegenerative diseases. GAPDH colocalizes with α-synuclein in amyloid aggregates in post-mortem tissue of patients with sporadic Parkinson disease and promotes the formation of Lewy body-like inclusions in cell culture. In a previous work, we showed that glycosaminoglycan-induced GAPDH prefibrillar species accelerate the conversion of α-synuclein to fibrils. However, it remains to be determined whether the interplay among glycosaminoglycans, GAPDH, and α-synuclein has a role in pathological states. Here, we demonstrate that the toxic effect exerted by α-synuclein oligomers in dopaminergic cell culture is abolished in the presence of GAPDH prefibrillar species. Structural analysis of prefibrillar GAPDH performed by small angle x-ray scattering showed a particle compatible with a protofibril. This protofibril is shaped as a cylinder 22 nm long and a cross-section diameter of 12 nm. Using biocomputational techniques, we obtained the first all-atom model of the GAPDH protofibril, which was validated by cross-linking coupled to mass spectrometry experiments. Because GAPDH can be secreted outside the cell where glycosaminoglycans are present, it seems plausible that GAPDH protofibrils could be assembled in the extracellular space kidnapping α-synuclein toxic oligomers. Thus, the role of GAPDH protofibrils in neuronal proteostasis must be considered. The data reported here could open alternative ways in the development of therapeutic strategies against synucleinopathies like Parkinson disease.
Fil: Avila, Cesar Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentina
Fil: Torres Bugeau, Clarisa Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentina
Fil: Barbosa, Leandro R. S.. Universidade de Sao Paulo; Brasil
Fil: Morandé Sales, Elisa. Universidade de Sao Paulo; Brasil
Fil: Ouidja, Mohand O.. Inserm; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Socias, Sergio Benjamin. Inserm; Francia
Fil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (p); Argentina. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas; Argentina
Fil: Raisman Vozari, Rita. Universidade de Sao Paulo; Brasil
Fil: Papy Garcia, Dulce. Centre National de la Recherche Scientifique; Francia
Fil: Itri, Rosangela. Universidade de Sao Paulo; Brasil
Fil: Chehin, Rosana Nieves. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentina
Materia
Alpha-Synuclein
Parkinson'S Disease
Molecular Modeling
X-Ray Scattering
Cell Permeabilization
Protein Aggregation
Glycosaminoglycan
Glyceraldehyde-3-Phosphate Dehydrogenase
Protofibril Structure
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/12850
Acceder
id CONICETDig_4e1af353d420610bd800f770024aaa14
oai_identifier_str oai:ri.conicet.gov.ar:11336/12850
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species ToxicityAvila, Cesar LuisTorres Bugeau, Clarisa MariaBarbosa, Leandro R. S.Morandé Sales, ElisaOuidja, Mohand O.Socias, Sergio BenjaminCelej, Maria SoledadRaisman Vozari, RitaPapy Garcia, DulceItri, RosangelaChehin, Rosana NievesAlpha-SynucleinParkinson'S DiseaseMolecular ModelingX-Ray ScatteringCell PermeabilizationProtein AggregationGlycosaminoglycanGlyceraldehyde-3-Phosphate DehydrogenaseProtofibril Structurehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme that has been associated with neurodegenerative diseases. GAPDH colocalizes with α-synuclein in amyloid aggregates in post-mortem tissue of patients with sporadic Parkinson disease and promotes the formation of Lewy body-like inclusions in cell culture. In a previous work, we showed that glycosaminoglycan-induced GAPDH prefibrillar species accelerate the conversion of α-synuclein to fibrils. However, it remains to be determined whether the interplay among glycosaminoglycans, GAPDH, and α-synuclein has a role in pathological states. Here, we demonstrate that the toxic effect exerted by α-synuclein oligomers in dopaminergic cell culture is abolished in the presence of GAPDH prefibrillar species. Structural analysis of prefibrillar GAPDH performed by small angle x-ray scattering showed a particle compatible with a protofibril. This protofibril is shaped as a cylinder 22 nm long and a cross-section diameter of 12 nm. Using biocomputational techniques, we obtained the first all-atom model of the GAPDH protofibril, which was validated by cross-linking coupled to mass spectrometry experiments. Because GAPDH can be secreted outside the cell where glycosaminoglycans are present, it seems plausible that GAPDH protofibrils could be assembled in the extracellular space kidnapping α-synuclein toxic oligomers. Thus, the role of GAPDH protofibrils in neuronal proteostasis must be considered. The data reported here could open alternative ways in the development of therapeutic strategies against synucleinopathies like Parkinson disease.Fil: Avila, Cesar Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Torres Bugeau, Clarisa Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Barbosa, Leandro R. S.. Universidade de Sao Paulo; BrasilFil: Morandé Sales, Elisa. Universidade de Sao Paulo; BrasilFil: Ouidja, Mohand O.. Inserm; Francia. Centre National de la Recherche Scientifique; FranciaFil: Socias, Sergio Benjamin. Inserm; FranciaFil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (p); Argentina. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas; ArgentinaFil: Raisman Vozari, Rita. Universidade de Sao Paulo; BrasilFil: Papy Garcia, Dulce. Centre National de la Recherche Scientifique; FranciaFil: Itri, Rosangela. Universidade de Sao Paulo; BrasilFil: Chehin, Rosana Nieves. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaAmerican Society for Biochemistry and Molecular Biology2014-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/12850Avila, Cesar Luis; Torres Bugeau, Clarisa Maria; Barbosa, Leandro R. S.; Morandé Sales, Elisa; Ouidja, Mohand O.; et al.; Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry; 289; 20; 5-2014; 13838-138500021-9258enginfo:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/289/20/13838info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M113.544288info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:44:14Zoai:ri.conicet.gov.ar:11336/12850instacron: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:34982025-10-22 11:44:14.726CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
title Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
spellingShingle Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
Avila, Cesar Luis
Alpha-Synuclein
Parkinson'S Disease
Molecular Modeling
X-Ray Scattering
Cell Permeabilization
Protein Aggregation
Glycosaminoglycan
Glyceraldehyde-3-Phosphate Dehydrogenase
Protofibril Structure
title_short Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
title_full Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
title_fullStr Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
title_full_unstemmed Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
title_sort Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
dc.creator.none.fl_str_mv Avila, Cesar Luis
Torres Bugeau, Clarisa Maria
Barbosa, Leandro R. S.
Morandé Sales, Elisa
Ouidja, Mohand O.
Socias, Sergio Benjamin
Celej, Maria Soledad
Raisman Vozari, Rita
Papy Garcia, Dulce
Itri, Rosangela
Chehin, Rosana Nieves
author Avila, Cesar Luis
author_facet Avila, Cesar Luis
Torres Bugeau, Clarisa Maria
Barbosa, Leandro R. S.
Morandé Sales, Elisa
Ouidja, Mohand O.
Socias, Sergio Benjamin
Celej, Maria Soledad
Raisman Vozari, Rita
Papy Garcia, Dulce
Itri, Rosangela
Chehin, Rosana Nieves
author_role author
author2 Torres Bugeau, Clarisa Maria
Barbosa, Leandro R. S.
Morandé Sales, Elisa
Ouidja, Mohand O.
Socias, Sergio Benjamin
Celej, Maria Soledad
Raisman Vozari, Rita
Papy Garcia, Dulce
Itri, Rosangela
Chehin, Rosana Nieves
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alpha-Synuclein
Parkinson'S Disease
Molecular Modeling
X-Ray Scattering
Cell Permeabilization
Protein Aggregation
Glycosaminoglycan
Glyceraldehyde-3-Phosphate Dehydrogenase
Protofibril Structure
topic Alpha-Synuclein
Parkinson'S Disease
Molecular Modeling
X-Ray Scattering
Cell Permeabilization
Protein Aggregation
Glycosaminoglycan
Glyceraldehyde-3-Phosphate Dehydrogenase
Protofibril Structure
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme that has been associated with neurodegenerative diseases. GAPDH colocalizes with α-synuclein in amyloid aggregates in post-mortem tissue of patients with sporadic Parkinson disease and promotes the formation of Lewy body-like inclusions in cell culture. In a previous work, we showed that glycosaminoglycan-induced GAPDH prefibrillar species accelerate the conversion of α-synuclein to fibrils. However, it remains to be determined whether the interplay among glycosaminoglycans, GAPDH, and α-synuclein has a role in pathological states. Here, we demonstrate that the toxic effect exerted by α-synuclein oligomers in dopaminergic cell culture is abolished in the presence of GAPDH prefibrillar species. Structural analysis of prefibrillar GAPDH performed by small angle x-ray scattering showed a particle compatible with a protofibril. This protofibril is shaped as a cylinder 22 nm long and a cross-section diameter of 12 nm. Using biocomputational techniques, we obtained the first all-atom model of the GAPDH protofibril, which was validated by cross-linking coupled to mass spectrometry experiments. Because GAPDH can be secreted outside the cell where glycosaminoglycans are present, it seems plausible that GAPDH protofibrils could be assembled in the extracellular space kidnapping α-synuclein toxic oligomers. Thus, the role of GAPDH protofibrils in neuronal proteostasis must be considered. The data reported here could open alternative ways in the development of therapeutic strategies against synucleinopathies like Parkinson disease.
Fil: Avila, Cesar Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentina
Fil: Torres Bugeau, Clarisa Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentina
Fil: Barbosa, Leandro R. S.. Universidade de Sao Paulo; Brasil
Fil: Morandé Sales, Elisa. Universidade de Sao Paulo; Brasil
Fil: Ouidja, Mohand O.. Inserm; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Socias, Sergio Benjamin. Inserm; Francia
Fil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (p); Argentina. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas; Argentina
Fil: Raisman Vozari, Rita. Universidade de Sao Paulo; Brasil
Fil: Papy Garcia, Dulce. Centre National de la Recherche Scientifique; Francia
Fil: Itri, Rosangela. Universidade de Sao Paulo; Brasil
Fil: Chehin, Rosana Nieves. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentina
description Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme that has been associated with neurodegenerative diseases. GAPDH colocalizes with α-synuclein in amyloid aggregates in post-mortem tissue of patients with sporadic Parkinson disease and promotes the formation of Lewy body-like inclusions in cell culture. In a previous work, we showed that glycosaminoglycan-induced GAPDH prefibrillar species accelerate the conversion of α-synuclein to fibrils. However, it remains to be determined whether the interplay among glycosaminoglycans, GAPDH, and α-synuclein has a role in pathological states. Here, we demonstrate that the toxic effect exerted by α-synuclein oligomers in dopaminergic cell culture is abolished in the presence of GAPDH prefibrillar species. Structural analysis of prefibrillar GAPDH performed by small angle x-ray scattering showed a particle compatible with a protofibril. This protofibril is shaped as a cylinder 22 nm long and a cross-section diameter of 12 nm. Using biocomputational techniques, we obtained the first all-atom model of the GAPDH protofibril, which was validated by cross-linking coupled to mass spectrometry experiments. Because GAPDH can be secreted outside the cell where glycosaminoglycans are present, it seems plausible that GAPDH protofibrils could be assembled in the extracellular space kidnapping α-synuclein toxic oligomers. Thus, the role of GAPDH protofibrils in neuronal proteostasis must be considered. The data reported here could open alternative ways in the development of therapeutic strategies against synucleinopathies like Parkinson disease.
publishDate 2014
dc.date.none.fl_str_mv 2014-05
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/11336/12850
Avila, Cesar Luis; Torres Bugeau, Clarisa Maria; Barbosa, Leandro R. S.; Morandé Sales, Elisa; Ouidja, Mohand O.; et al.; Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry; 289; 20; 5-2014; 13838-13850
0021-9258
url http://hdl.handle.net/11336/12850
identifier_str_mv Avila, Cesar Luis; Torres Bugeau, Clarisa Maria; Barbosa, Leandro R. S.; Morandé Sales, Elisa; Ouidja, Mohand O.; et al.; Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry; 289; 20; 5-2014; 13838-13850
0021-9258
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/289/20/13838
info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M113.544288
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
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 12.982451

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