α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner
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...
| Autores: | , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2014 |
| País: | Argentina |
| Institución: | Consejo Nacional de Investigaciones Científicas y Técnicas |
| Repositorio: | CONICET Digital (CONICET) |
| Idioma: | inglés |
| OAI Identifier: | oai:ri.conicet.gov.ar:11336/29424 |
| Acceso en línea: | http://hdl.handle.net/11336/29424 |
| Access Level: | acceso abierto |
| Palabra clave: | Α-Synuclein Aggregation Parkinson'S Disease Phosphorylation Rab Gtpase https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
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Argentina |
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| 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 https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| 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 https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| topic |
Α-Synuclein Aggregation Parkinson'S Disease Phosphorylation Rab Gtpase https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| 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 |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
| repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
| _version_ |
1799196061085990912 |
| 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 Técnicas2024-05-08T14:13:21Zoai: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:34982024-05-08 14:13:21.864CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
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15,812429 |