α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Autores
Yin, Guowei; Lopes da Fonseca, Tomas; Eisbach, Sibylle E.; Anduaga, Ane Martin; Breda, Carlo; Orcellet, Maria Laura; Szegő, Eva M.; Guerreiro, Patria; Lázaro, Diana F.; Braus, Gerhard H.; Fernandez, Claudio Oscar; Griesinger, Christian; Becker, Stefan; Goody, Roger S.; Itzen, Aymelt; Giorgini, Flaviano; Outeiro, Tiago F.; Zweckstetter, Markus
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 – the Drosophila ortholog of Rab8a – ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS–Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.
Fil: Yin, Guowei. Max Planck Institute Of Biochemistry.; Alemania
Fil: Lopes da Fonseca, Tomas. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Eisbach, Sibylle E.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Anduaga, Ane Martin. University of Leicester; Reino Unido
Fil: Breda, Carlo. University of Leicester; Reino Unido
Fil: Orcellet, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Szegő, Eva M.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Guerreiro, Patria. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Lázaro, Diana F.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Braus, Gerhard H.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Griesinger, Christian. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Becker, Stefan. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Goody, Roger S.. Max-Planck-Institute of Molecular Physiology; Alemania
Fil: Itzen, Aymelt. Universitat Technical Zu Munich; Alemania. Max-Planck-Institute of Molecular Physiology; Alemania
Fil: Giorgini, Flaviano. University of Leicester; Reino Unido
Fil: Outeiro, Tiago F.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry; Alemania. German Center for Neurodegenerative Diseases; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Materia
Α-Synuclein
Aggregation
Parkinson'S Disease
Phosphorylation
Rab Gtpase
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/29424
Acceder
id CONICETDig_ddaf308e15e301281e91a3597ddf3d23
oai_identifier_str oai:ri.conicet.gov.ar:11336/29424
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent mannerYin, GuoweiLopes da Fonseca, TomasEisbach, Sibylle E.Anduaga, Ane MartinBreda, CarloOrcellet, Maria LauraSzegő, Eva M.Guerreiro, PatriaLázaro, Diana F.Braus, Gerhard H.Fernandez, Claudio OscarGriesinger, ChristianBecker, StefanGoody, Roger S.Itzen, AymeltGiorgini, FlavianoOuteiro, Tiago F.Zweckstetter, MarkusΑ-SynucleinAggregationParkinson'S DiseasePhosphorylationRab Gtpasehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 – the Drosophila ortholog of Rab8a – ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS–Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.Fil: Yin, Guowei. Max Planck Institute Of Biochemistry.; AlemaniaFil: Lopes da Fonseca, Tomas. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; AlemaniaFil: Eisbach, Sibylle E.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; AlemaniaFil: Anduaga, Ane Martin. University of Leicester; Reino UnidoFil: Breda, Carlo. University of Leicester; Reino UnidoFil: Orcellet, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Szegő, Eva M.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; AlemaniaFil: Guerreiro, Patria. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; AlemaniaFil: Lázaro, Diana F.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; AlemaniaFil: Braus, Gerhard H.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; AlemaniaFil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Griesinger, Christian. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Becker, Stefan. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Goody, Roger S.. Max-Planck-Institute of Molecular Physiology; AlemaniaFil: Itzen, Aymelt. Universitat Technical Zu Munich; Alemania. Max-Planck-Institute of Molecular Physiology; AlemaniaFil: Giorgini, Flaviano. University of Leicester; Reino UnidoFil: Outeiro, Tiago F.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; AlemaniaFil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry; Alemania. German Center for Neurodegenerative Diseases; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; AlemaniaAcademic Press Inc Elsevier Science2014-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/29424Yin, Guowei; Lopes da Fonseca, Tomas; Eisbach, Sibylle E.; Anduaga, Ane Martin; Breda, Carlo; et al.; α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner; Academic Press Inc Elsevier Science; Neurobiology Of Disease; 70; 6-2014; 149-1611095-953X0969-9961CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S096999611400182Xinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2014.06.018info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:05:22Zoai:ri.conicet.gov.ar:11336/29424instacron: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 10:05:22.396CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner
title α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner
spellingShingle α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner
Yin, Guowei
Α-Synuclein
Aggregation
Parkinson'S Disease
Phosphorylation
Rab Gtpase
title_short α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner
title_full α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner
title_fullStr α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner
title_full_unstemmed α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner
title_sort α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner
dc.creator.none.fl_str_mv Yin, Guowei
Lopes da Fonseca, Tomas
Eisbach, Sibylle E.
Anduaga, Ane Martin
Breda, Carlo
Orcellet, Maria Laura
Szegő, Eva M.
Guerreiro, Patria
Lázaro, Diana F.
Braus, Gerhard H.
Fernandez, Claudio Oscar
Griesinger, Christian
Becker, Stefan
Goody, Roger S.
Itzen, Aymelt
Giorgini, Flaviano
Outeiro, Tiago F.
Zweckstetter, Markus
author Yin, Guowei
author_facet Yin, Guowei
Lopes da Fonseca, Tomas
Eisbach, Sibylle E.
Anduaga, Ane Martin
Breda, Carlo
Orcellet, Maria Laura
Szegő, Eva M.
Guerreiro, Patria
Lázaro, Diana F.
Braus, Gerhard H.
Fernandez, Claudio Oscar
Griesinger, Christian
Becker, Stefan
Goody, Roger S.
Itzen, Aymelt
Giorgini, Flaviano
Outeiro, Tiago F.
Zweckstetter, Markus
author_role author
author2 Lopes da Fonseca, Tomas
Eisbach, Sibylle E.
Anduaga, Ane Martin
Breda, Carlo
Orcellet, Maria Laura
Szegő, Eva M.
Guerreiro, Patria
Lázaro, Diana F.
Braus, Gerhard H.
Fernandez, Claudio Oscar
Griesinger, Christian
Becker, Stefan
Goody, Roger S.
Itzen, Aymelt
Giorgini, Flaviano
Outeiro, Tiago F.
Zweckstetter, Markus
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Α-Synuclein
Aggregation
Parkinson'S Disease
Phosphorylation
Rab Gtpase
topic Α-Synuclein
Aggregation
Parkinson'S Disease
Phosphorylation
Rab Gtpase
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 – the Drosophila ortholog of Rab8a – ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS–Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.
Fil: Yin, Guowei. Max Planck Institute Of Biochemistry.; Alemania
Fil: Lopes da Fonseca, Tomas. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Eisbach, Sibylle E.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Anduaga, Ane Martin. University of Leicester; Reino Unido
Fil: Breda, Carlo. University of Leicester; Reino Unido
Fil: Orcellet, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Szegő, Eva M.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Guerreiro, Patria. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Lázaro, Diana F.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Braus, Gerhard H.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Griesinger, Christian. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Becker, Stefan. Max Planck Institute for Biophysical Chemistry; Alemania
Fil: Goody, Roger S.. Max-Planck-Institute of Molecular Physiology; Alemania
Fil: Itzen, Aymelt. Universitat Technical Zu Munich; Alemania. Max-Planck-Institute of Molecular Physiology; Alemania
Fil: Giorgini, Flaviano. University of Leicester; Reino Unido
Fil: Outeiro, Tiago F.. Universität Göttingen; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry; Alemania. German Center for Neurodegenerative Diseases; Alemania. Research Center Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
description Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 – the Drosophila ortholog of Rab8a – ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS–Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.
publishDate 2014
dc.date.none.fl_str_mv 2014-06
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/11336/29424
Yin, Guowei; Lopes da Fonseca, Tomas; Eisbach, Sibylle E.; Anduaga, Ane Martin; Breda, Carlo; et al.; α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner; Academic Press Inc Elsevier Science; Neurobiology Of Disease; 70; 6-2014; 149-161
1095-953X
0969-9961
CONICET Digital
CONICET
url http://hdl.handle.net/11336/29424
identifier_str_mv Yin, Guowei; Lopes da Fonseca, Tomas; Eisbach, Sibylle E.; Anduaga, Ane Martin; Breda, Carlo; et al.; α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner; Academic Press Inc Elsevier Science; Neurobiology Of Disease; 70; 6-2014; 149-161
1095-953X
0969-9961
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S096999611400182X
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2014.06.018
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Academic Press Inc Elsevier Science
publisher.none.fl_str_mv Academic Press Inc Elsevier Science
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 13.13397

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