Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation

Autores
Fonseca Ornelas, Luis; Eisbach, Sybille E.; Paulat, Maria; Giller, Karin; Fernandez, Claudio Oscar; Outeiro, Tiago F; Becker, Stefan; Zweckstetter, Markus
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
α-synuclein is an abundant presynaptic protein that is important for regulation of synaptic vesicle trafficking, and whose misfolding plays a key role in Parkinson’s disease. While α-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded α-synuclein might therefore interfere with α-synuclein-induced neurotoxicity. Here we show that several small molecules, which delay aggregation of α-synuclein in solution, including the Parkinson’s disease drug selegiline, fail to interfere with misfolding of vesicle-bound α-synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound α-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small-molecule-mediated stabilization of helical vesicle-bound α-synuclein opens new possibilities to target Parkinson’s disease and related synucleinopathies
Fil: Fonseca Ornelas, Luis. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Eisbach, Sybille E.. University Medicine; Alemania
Fil: Paulat, Maria. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Giller, Karin. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Fernandez, Claudio Oscar. Universidad Nacional de Rosario; Argentina. Instituto de Investigaciones para el Descubrimiento de Farmacos de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Outeiro, Tiago F. University Medicine; Alemania. University Medical Center; Alemania
Fil: Becker, Stefan. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry; Alemania. University Medical Center; Alemania. German Center for Neurodegenerative Diseases; Alemania
Materia
amiloide
inhibicion
sinucleina
PcTS
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:11336/29704
Acceder
id CONICETDig_5189fc3917274cfe2b1af8c123211222
oai_identifier_str oai:ri.conicet.gov.ar:11336/29704
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregationFonseca Ornelas, LuisEisbach, Sybille E.Paulat, MariaGiller, KarinFernandez, Claudio OscarOuteiro, Tiago FBecker, StefanZweckstetter, MarkusamiloideinhibicionsinucleinaPcTShttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1α-synuclein is an abundant presynaptic protein that is important for regulation of synaptic vesicle trafficking, and whose misfolding plays a key role in Parkinson’s disease. While α-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded α-synuclein might therefore interfere with α-synuclein-induced neurotoxicity. Here we show that several small molecules, which delay aggregation of α-synuclein in solution, including the Parkinson’s disease drug selegiline, fail to interfere with misfolding of vesicle-bound α-synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound α-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small-molecule-mediated stabilization of helical vesicle-bound α-synuclein opens new possibilities to target Parkinson’s disease and related synucleinopathiesFil: Fonseca Ornelas, Luis. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Eisbach, Sybille E.. University Medicine; AlemaniaFil: Paulat, Maria. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Giller, Karin. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Fernandez, Claudio Oscar. Universidad Nacional de Rosario; Argentina. Instituto de Investigaciones para el Descubrimiento de Farmacos de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Outeiro, Tiago F. University Medicine; Alemania. University Medical Center; AlemaniaFil: Becker, Stefan. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry; Alemania. University Medical Center; Alemania. German Center for Neurodegenerative Diseases; AlemaniaNature Publishing Group2014-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/29704Fonseca Ornelas, Luis; Eisbach, Sybille E.; Paulat, Maria; Giller, Karin; Fernandez, Claudio Oscar; et al.; Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation; Nature Publishing Group; Nature Communications; 5; 12-2014; 1-112041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms6857info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ncomms6857info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:09:39Zoai:ri.conicet.gov.ar:11336/29704instacron: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 10:09:39.903CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation
title Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation
spellingShingle Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation
Fonseca Ornelas, Luis
amiloide
inhibicion
sinucleina
PcTS
title_short Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation
title_full Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation
title_fullStr Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation
title_full_unstemmed Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation
title_sort Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation
dc.creator.none.fl_str_mv Fonseca Ornelas, Luis
Eisbach, Sybille E.
Paulat, Maria
Giller, Karin
Fernandez, Claudio Oscar
Outeiro, Tiago F
Becker, Stefan
Zweckstetter, Markus
author Fonseca Ornelas, Luis
author_facet Fonseca Ornelas, Luis
Eisbach, Sybille E.
Paulat, Maria
Giller, Karin
Fernandez, Claudio Oscar
Outeiro, Tiago F
Becker, Stefan
Zweckstetter, Markus
author_role author
author2 Eisbach, Sybille E.
Paulat, Maria
Giller, Karin
Fernandez, Claudio Oscar
Outeiro, Tiago F
Becker, Stefan
Zweckstetter, Markus
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv amiloide
inhibicion
sinucleina
PcTS
topic amiloide
inhibicion
sinucleina
PcTS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv α-synuclein is an abundant presynaptic protein that is important for regulation of synaptic vesicle trafficking, and whose misfolding plays a key role in Parkinson’s disease. While α-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded α-synuclein might therefore interfere with α-synuclein-induced neurotoxicity. Here we show that several small molecules, which delay aggregation of α-synuclein in solution, including the Parkinson’s disease drug selegiline, fail to interfere with misfolding of vesicle-bound α-synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound α-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small-molecule-mediated stabilization of helical vesicle-bound α-synuclein opens new possibilities to target Parkinson’s disease and related synucleinopathies
Fil: Fonseca Ornelas, Luis. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Eisbach, Sybille E.. University Medicine; Alemania
Fil: Paulat, Maria. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Giller, Karin. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Fernandez, Claudio Oscar. Universidad Nacional de Rosario; Argentina. Instituto de Investigaciones para el Descubrimiento de Farmacos de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Outeiro, Tiago F. University Medicine; Alemania. University Medical Center; Alemania
Fil: Becker, Stefan. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry; Alemania. University Medical Center; Alemania. German Center for Neurodegenerative Diseases; Alemania
description α-synuclein is an abundant presynaptic protein that is important for regulation of synaptic vesicle trafficking, and whose misfolding plays a key role in Parkinson’s disease. While α-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded α-synuclein might therefore interfere with α-synuclein-induced neurotoxicity. Here we show that several small molecules, which delay aggregation of α-synuclein in solution, including the Parkinson’s disease drug selegiline, fail to interfere with misfolding of vesicle-bound α-synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound α-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small-molecule-mediated stabilization of helical vesicle-bound α-synuclein opens new possibilities to target Parkinson’s disease and related synucleinopathies
publishDate 2014
dc.date.none.fl_str_mv 2014-12
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/11336/29704
Fonseca Ornelas, Luis; Eisbach, Sybille E.; Paulat, Maria; Giller, Karin; Fernandez, Claudio Oscar; et al.; Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation; Nature Publishing Group; Nature Communications; 5; 12-2014; 1-11
2041-1723
CONICET Digital
CONICET
url http://hdl.handle.net/11336/29704
identifier_str_mv Fonseca Ornelas, Luis; Eisbach, Sybille E.; Paulat, Maria; Giller, Karin; Fernandez, Claudio Oscar; et al.; Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation; Nature Publishing Group; Nature Communications; 5; 12-2014; 1-11
2041-1723
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms6857
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ncomms6857
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 Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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_ 1842270090347675648
score 13.13397

Publicaciones similares