Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation

Autores
Fauerbach, Jonathan Arturo; Yushchenko, Dmytro A.; Shahmoradian, Sarah H.; Chiu, Wah; Jovin, Thomas M.; Jares, Elizabeth Andrea
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ∼0.3–0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity.
Fil: Fauerbach, Jonathan Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; Argentina
Fil: Yushchenko, Dmytro A.. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Shahmoradian, Sarah H.. Baylor College of Medicine; Estados Unidos
Fil: Chiu, Wah. Baylor College of Medicine; Estados Unidos
Fil: Jovin, Thomas M.. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Jares, Elizabeth Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; Argentina
Materia
Synuclein
Supramolecular
Aggregation
Non-Amyloid
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:11336/68169
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein AggregationFauerbach, Jonathan ArturoYushchenko, Dmytro A.Shahmoradian, Sarah H.Chiu, WahJovin, Thomas M.Jares, Elizabeth AndreaSynucleinSupramolecularAggregationNon-Amyloidhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ∼0.3–0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity.Fil: Fauerbach, Jonathan Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; ArgentinaFil: Yushchenko, Dmytro A.. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Shahmoradian, Sarah H.. Baylor College of Medicine; Estados UnidosFil: Chiu, Wah. Baylor College of Medicine; Estados UnidosFil: Jovin, Thomas M.. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Jares, Elizabeth Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; ArgentinaCell Press2012-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/68169Fauerbach, Jonathan Arturo; Yushchenko, Dmytro A.; Shahmoradian, Sarah H.; Chiu, Wah; Jovin, Thomas M.; et al.; Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation; Cell Press; Biophysical Journal; 102; 5; 3-2012; 1127-11360006-3495CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0006349512001683info:eu-repo/semantics/altIdentifier/doi/10.1016%2Fj.bpj.2012.01.051info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:43:20Zoai:ri.conicet.gov.ar:11336/68169instacron: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 09:43:21.209CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation
title Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation
spellingShingle Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation
Fauerbach, Jonathan Arturo
Synuclein
Supramolecular
Aggregation
Non-Amyloid
title_short Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation
title_full Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation
title_fullStr Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation
title_full_unstemmed Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation
title_sort Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation
dc.creator.none.fl_str_mv Fauerbach, Jonathan Arturo
Yushchenko, Dmytro A.
Shahmoradian, Sarah H.
Chiu, Wah
Jovin, Thomas M.
Jares, Elizabeth Andrea
author Fauerbach, Jonathan Arturo
author_facet Fauerbach, Jonathan Arturo
Yushchenko, Dmytro A.
Shahmoradian, Sarah H.
Chiu, Wah
Jovin, Thomas M.
Jares, Elizabeth Andrea
author_role author
author2 Yushchenko, Dmytro A.
Shahmoradian, Sarah H.
Chiu, Wah
Jovin, Thomas M.
Jares, Elizabeth Andrea
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Synuclein
Supramolecular
Aggregation
Non-Amyloid
topic Synuclein
Supramolecular
Aggregation
Non-Amyloid
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ∼0.3–0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity.
Fil: Fauerbach, Jonathan Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; Argentina
Fil: Yushchenko, Dmytro A.. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Shahmoradian, Sarah H.. Baylor College of Medicine; Estados Unidos
Fil: Chiu, Wah. Baylor College of Medicine; Estados Unidos
Fil: Jovin, Thomas M.. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Jares, Elizabeth Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; Argentina
description The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ∼0.3–0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity.
publishDate 2012
dc.date.none.fl_str_mv 2012-03
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/11336/68169
Fauerbach, Jonathan Arturo; Yushchenko, Dmytro A.; Shahmoradian, Sarah H.; Chiu, Wah; Jovin, Thomas M.; et al.; Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation; Cell Press; Biophysical Journal; 102; 5; 3-2012; 1127-1136
0006-3495
CONICET Digital
CONICET
url http://hdl.handle.net/11336/68169
identifier_str_mv Fauerbach, Jonathan Arturo; Yushchenko, Dmytro A.; Shahmoradian, Sarah H.; Chiu, Wah; Jovin, Thomas M.; et al.; Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation; Cell Press; Biophysical Journal; 102; 5; 3-2012; 1127-1136
0006-3495
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://linkinghub.elsevier.com/retrieve/pii/S0006349512001683
info:eu-repo/semantics/altIdentifier/doi/10.1016%2Fj.bpj.2012.01.051
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
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
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
_version_ 1842268595944423424
score 13.13397

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