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dc.contributor.author
Avila, Cesar Luis
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Torres Bugeau, Clarisa Maria
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Barbosa, Leandro R. S.
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Morandé Sales, Elisa
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Ouidja, Mohand O.
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Socias, Sergio Benjamin
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Celej, Maria Soledad
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Raisman Vozari, Rita
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Papy Garcia, Dulce
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Itri, Rosangela
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Chehin, Rosana Nieves
dc.date.available
2017-02-10T17:39:12Z
dc.date.issued
2014-05
dc.identifier.citation
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
dc.identifier.issn
0021-9258
dc.identifier.uri
http://hdl.handle.net/11336/12850
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Society for Biochemistry and Molecular Biology
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Alpha-Synuclein
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Parkinson'S Disease
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Molecular Modeling
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X-Ray Scattering
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Cell Permeabilization
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Protein Aggregation
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Glycosaminoglycan
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Glyceraldehyde-3-Phosphate Dehydrogenase
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Protofibril Structure
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Biofísica
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-02-09T18:24:14Z
dc.journal.volume
289
dc.journal.number
20
dc.journal.pagination
13838-13850
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Bethesda
dc.description.fil
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
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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
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Fil: Barbosa, Leandro R. S.. Universidade de Sao Paulo; Brasil
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Fil: Morandé Sales, Elisa. Universidade de Sao Paulo; Brasil
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Fil: Ouidja, Mohand O.. Inserm; Francia. Centre National de la Recherche Scientifique; Francia
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Fil: Socias, Sergio Benjamin. Inserm; Francia
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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
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Fil: Raisman Vozari, Rita. Universidade de Sao Paulo; Brasil
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Fil: Papy Garcia, Dulce. Centre National de la Recherche Scientifique; Francia
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Fil: Itri, Rosangela. Universidade de Sao Paulo; Brasil
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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
dc.journal.title
Journal of Biological Chemistry
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/289/20/13838
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info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1074/jbc.M113.544288