Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease

Autores: Toth, Gergely; Gardai, Shyra J.; Zago, Wagner; Bertoncini, Carlos Walter; Cremades, Nunilo; Roy, Susan L.; Tambe, Mitali A.; Roche, Jean Christophe; Galvagnion, Celine; Skibinski, Gaia; Finkbeiner, Steven; Bova, Michael; Regnstrom, Karin; Chiou, San-San; Johnston, Jennifer; Callaway, Kari; Anderson, John P.; Jobling, Michael F.; Buel, Alexander K.; Yednock, Ted A.; Knowles, Tuomas P. J.; Vendruscolo, Michele; Christodoulou, John; Dobson, Christopher M.; Schenk, Dale; McConlogue, LIsa
Año de publicación: 2014
Idioma: inglés
Tipo de recurso: artículo
Estado: versión publicada
Descripción: The misfolding of intrinsically disordered proteins such asa-synuclein, tau and the Abpeptide has been associated withmany highly debilitating neurodegenerative syndromes including Parkinson’s and Alzheimer’s diseases. Therapeutictargeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a majorchallenge because of their heterogeneous conformational properties. We show here that a combination of computationaland experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), thattargetsa-synuclein, a key protein in Parkinson’s disease. We found that this compound has substantial biological activity incellular models ofa-synuclein-mediated dysfunction, including rescue ofa-synuclein-induced disruption of vesicletrafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount ofa-synucleintargeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells.These results indicate that targetinga-synuclein by small molecules represents a promising approach to the developmentof therapeutic treatments of Parkinson’s disease and related conditions.
Fil: Toth, Gergely. University of Cambridge; Reino Unido. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Gardai, Shyra J.. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Zago, Wagner. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Bertoncini, Carlos Walter. University of Cambridge; Reino Unido. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cremades, Nunilo. University of Cambridge; Reino Unido
Fil: Roy, Susan L.. Purdue University; Estados Unidos
Fil: Tambe, Mitali A.. Purdue University; Estados Unidos
Fil: Roche, Jean Christophe. Purdue University; Estados Unidos
Fil: Galvagnion, Celine. University of Cambridge; Reino Unido
Fil: Skibinski, Gaia. Gladstone Institute of Neurological Disease. San Francisco; Estados Unidos. Taube-Koret Center for Neurodegenerative Disease Researc. San Francisco; Estados Unidos
Fil: Finkbeiner, Steven. Taube-Koret Center for Neurodegenerative Disease Researc. San Francisco; Estados Unidos. Gladstone Institute of Neurological Disease. San Francisco; Estados Unidos. Departments of Neurology and Physiology. San Francisco; Estados Unidos
Fil: Bova, Michael. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Regnstrom, Karin. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Chiou, San-San. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Johnston, Jennifer. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Callaway, Kari. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Anderson, John P.. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Jobling, Michael F.. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Buel, Alexander K.. University of Cambridge; Reino Unido
Fil: Yednock, Ted A.. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: Knowles, Tuomas P. J.. University of Cambridge; Reino Unido
Fil: Vendruscolo, Michele. University of Cambridge; Reino Unido
Fil: Christodoulou, John. University College London; Estados Unidos
Fil: Dobson, Christopher M.. University of Cambridge; Reino Unido
Fil: Schenk, Dale. Elan Pharmaceuticals. San Francisco; Estados Unidos
Fil: McConlogue, LIsa. Elan Pharmaceuticals. San Francisco; Estados Unidos
Materia: Descubrimiento de fármacos
Biología Estructural
Enfermedad de Parkinson
Química Computacional
Nivel de accesibilidad: acceso abierto
Condiciones de uso: https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
Institución: Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador: oai:ri.conicet.gov.ar:11336/31090

Acceder

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network_name_str	CONICET Digital (CONICET)
spelling	Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s DiseaseToth, GergelyGardai, Shyra J.Zago, WagnerBertoncini, Carlos WalterCremades, NuniloRoy, Susan L.Tambe, Mitali A.Roche, Jean ChristopheGalvagnion, CelineSkibinski, GaiaFinkbeiner, StevenBova, MichaelRegnstrom, KarinChiou, San-SanJohnston, JenniferCallaway, KariAnderson, John P.Jobling, Michael F.Buel, Alexander K.Yednock, Ted A.Knowles, Tuomas P. J.Vendruscolo, MicheleChristodoulou, JohnDobson, Christopher M.Schenk, DaleMcConlogue, LIsaDescubrimiento de fármacosBiología EstructuralEnfermedad de ParkinsonQuímica Computacionalhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The misfolding of intrinsically disordered proteins such asa-synuclein, tau and the Abpeptide has been associated withmany highly debilitating neurodegenerative syndromes including Parkinson’s and Alzheimer’s diseases. Therapeutictargeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a majorchallenge because of their heterogeneous conformational properties. We show here that a combination of computationaland experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), thattargetsa-synuclein, a key protein in Parkinson’s disease. We found that this compound has substantial biological activity incellular models ofa-synuclein-mediated dysfunction, including rescue ofa-synuclein-induced disruption of vesicletrafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount ofa-synucleintargeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells.These results indicate that targetinga-synuclein by small molecules represents a promising approach to the developmentof therapeutic treatments of Parkinson’s disease and related conditions.Fil: Toth, Gergely. University of Cambridge; Reino Unido. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Gardai, Shyra J.. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Zago, Wagner. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Bertoncini, Carlos Walter. University of Cambridge; Reino Unido. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cremades, Nunilo. University of Cambridge; Reino UnidoFil: Roy, Susan L.. Purdue University; Estados UnidosFil: Tambe, Mitali A.. Purdue University; Estados UnidosFil: Roche, Jean Christophe. Purdue University; Estados UnidosFil: Galvagnion, Celine. University of Cambridge; Reino UnidoFil: Skibinski, Gaia. Gladstone Institute of Neurological Disease. San Francisco; Estados Unidos. Taube-Koret Center for Neurodegenerative Disease Researc. San Francisco; Estados UnidosFil: Finkbeiner, Steven. Taube-Koret Center for Neurodegenerative Disease Researc. San Francisco; Estados Unidos. Gladstone Institute of Neurological Disease. San Francisco; Estados Unidos. Departments of Neurology and Physiology. San Francisco; Estados UnidosFil: Bova, Michael. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Regnstrom, Karin. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Chiou, San-San. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Johnston, Jennifer. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Callaway, Kari. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Anderson, John P.. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Jobling, Michael F.. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Buel, Alexander K.. University of Cambridge; Reino UnidoFil: Yednock, Ted A.. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: Knowles, Tuomas P. J.. University of Cambridge; Reino UnidoFil: Vendruscolo, Michele. University of Cambridge; Reino UnidoFil: Christodoulou, John. University College London; Estados UnidosFil: Dobson, Christopher M.. University of Cambridge; Reino UnidoFil: Schenk, Dale. Elan Pharmaceuticals. San Francisco; Estados UnidosFil: McConlogue, LIsa. Elan Pharmaceuticals. San Francisco; Estados UnidosPublic Library of Science2014-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/31090McConlogue, LIsa; Schenk, Dale; Dobson, Christopher M.; Christodoulou, John; Vendruscolo, Michele; Knowles, Tuomas P. J.; et al.; Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease; Public Library of Science; Plos One; 9; 2; 2-2014; 1-111932-6203CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087133info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0087133info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:23:05Zoai:ri.conicet.gov.ar:11336/31090instacron: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:34982025-09-29 10:23:05.681CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv	Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease
title	Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease
spellingShingle	Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease Toth, Gergely Descubrimiento de fármacos Biología Estructural Enfermedad de Parkinson Química Computacional
title_short	Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease
title_full	Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease
title_fullStr	Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease
title_full_unstemmed	Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease
title_sort	Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease
dc.creator.none.fl_str_mv	Toth, Gergely Gardai, Shyra J. Zago, Wagner Bertoncini, Carlos Walter Cremades, Nunilo Roy, Susan L. Tambe, Mitali A. Roche, Jean Christophe Galvagnion, Celine Skibinski, Gaia Finkbeiner, Steven Bova, Michael Regnstrom, Karin Chiou, San-San Johnston, Jennifer Callaway, Kari Anderson, John P. Jobling, Michael F. Buel, Alexander K. Yednock, Ted A. Knowles, Tuomas P. J. Vendruscolo, Michele Christodoulou, John Dobson, Christopher M. Schenk, Dale McConlogue, LIsa
author	Toth, Gergely
author_facet	Toth, Gergely Gardai, Shyra J. Zago, Wagner Bertoncini, Carlos Walter Cremades, Nunilo Roy, Susan L. Tambe, Mitali A. Roche, Jean Christophe Galvagnion, Celine Skibinski, Gaia Finkbeiner, Steven Bova, Michael Regnstrom, Karin Chiou, San-San Johnston, Jennifer Callaway, Kari Anderson, John P. Jobling, Michael F. Buel, Alexander K. Yednock, Ted A. Knowles, Tuomas P. J. Vendruscolo, Michele Christodoulou, John Dobson, Christopher M. Schenk, Dale McConlogue, LIsa
author_role	author
author2	Gardai, Shyra J. Zago, Wagner Bertoncini, Carlos Walter Cremades, Nunilo Roy, Susan L. Tambe, Mitali A. Roche, Jean Christophe Galvagnion, Celine Skibinski, Gaia Finkbeiner, Steven Bova, Michael Regnstrom, Karin Chiou, San-San Johnston, Jennifer Callaway, Kari Anderson, John P. Jobling, Michael F. Buel, Alexander K. Yednock, Ted A. Knowles, Tuomas P. J. Vendruscolo, Michele Christodoulou, John Dobson, Christopher M. Schenk, Dale McConlogue, LIsa
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Descubrimiento de fármacos Biología Estructural Enfermedad de Parkinson Química Computacional
topic	Descubrimiento de fármacos Biología Estructural Enfermedad de Parkinson Química Computacional
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 misfolding of intrinsically disordered proteins such asa-synuclein, tau and the Abpeptide has been associated withmany highly debilitating neurodegenerative syndromes including Parkinson’s and Alzheimer’s diseases. Therapeutictargeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a majorchallenge because of their heterogeneous conformational properties. We show here that a combination of computationaland experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), thattargetsa-synuclein, a key protein in Parkinson’s disease. We found that this compound has substantial biological activity incellular models ofa-synuclein-mediated dysfunction, including rescue ofa-synuclein-induced disruption of vesicletrafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount ofa-synucleintargeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells.These results indicate that targetinga-synuclein by small molecules represents a promising approach to the developmentof therapeutic treatments of Parkinson’s disease and related conditions. Fil: Toth, Gergely. University of Cambridge; Reino Unido. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Gardai, Shyra J.. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Zago, Wagner. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Bertoncini, Carlos Walter. University of Cambridge; Reino Unido. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cremades, Nunilo. University of Cambridge; Reino Unido Fil: Roy, Susan L.. Purdue University; Estados Unidos Fil: Tambe, Mitali A.. Purdue University; Estados Unidos Fil: Roche, Jean Christophe. Purdue University; Estados Unidos Fil: Galvagnion, Celine. University of Cambridge; Reino Unido Fil: Skibinski, Gaia. Gladstone Institute of Neurological Disease. San Francisco; Estados Unidos. Taube-Koret Center for Neurodegenerative Disease Researc. San Francisco; Estados Unidos Fil: Finkbeiner, Steven. Taube-Koret Center for Neurodegenerative Disease Researc. San Francisco; Estados Unidos. Gladstone Institute of Neurological Disease. San Francisco; Estados Unidos. Departments of Neurology and Physiology. San Francisco; Estados Unidos Fil: Bova, Michael. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Regnstrom, Karin. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Chiou, San-San. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Johnston, Jennifer. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Callaway, Kari. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Anderson, John P.. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Jobling, Michael F.. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Buel, Alexander K.. University of Cambridge; Reino Unido Fil: Yednock, Ted A.. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: Knowles, Tuomas P. J.. University of Cambridge; Reino Unido Fil: Vendruscolo, Michele. University of Cambridge; Reino Unido Fil: Christodoulou, John. University College London; Estados Unidos Fil: Dobson, Christopher M.. University of Cambridge; Reino Unido Fil: Schenk, Dale. Elan Pharmaceuticals. San Francisco; Estados Unidos Fil: McConlogue, LIsa. Elan Pharmaceuticals. San Francisco; Estados Unidos
description	The misfolding of intrinsically disordered proteins such asa-synuclein, tau and the Abpeptide has been associated withmany highly debilitating neurodegenerative syndromes including Parkinson’s and Alzheimer’s diseases. Therapeutictargeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a majorchallenge because of their heterogeneous conformational properties. We show here that a combination of computationaland experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), thattargetsa-synuclein, a key protein in Parkinson’s disease. We found that this compound has substantial biological activity incellular models ofa-synuclein-mediated dysfunction, including rescue ofa-synuclein-induced disruption of vesicletrafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount ofa-synucleintargeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells.These results indicate that targetinga-synuclein by small molecules represents a promising approach to the developmentof therapeutic treatments of Parkinson’s disease and related conditions.
publishDate	2014
dc.date.none.fl_str_mv	2014-02
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/11336/31090 McConlogue, LIsa; Schenk, Dale; Dobson, Christopher M.; Christodoulou, John; Vendruscolo, Michele; Knowles, Tuomas P. J.; et al.; Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease; Public Library of Science; Plos One; 9; 2; 2-2014; 1-11 1932-6203 CONICET Digital CONICET
url	http://hdl.handle.net/11336/31090
identifier_str_mv	McConlogue, LIsa; Schenk, Dale; Dobson, Christopher M.; Christodoulou, John; Vendruscolo, Michele; Knowles, Tuomas P. J.; et al.; Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease; Public Library of Science; Plos One; 9; 2; 2-2014; 1-11 1932-6203 CONICET Digital CONICET
dc.language.none.fl_str_mv	eng
language	eng
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dc.format.none.fl_str_mv	application/pdf application/pdf
dc.publisher.none.fl_str_mv	Public Library of Science
publisher.none.fl_str_mv	Public Library of Science
dc.source.none.fl_str_mv	reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas
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repository.mail.fl_str_mv	dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease

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