The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity

Parkinson's disease is associated with intracellular α-synuclein accumulation and ventral midbrain dopaminergic neuronal death in the Substantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has...

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Autores: Kim, Hanna, Calatayud Aristoy, Carles, Guha, Sanjib, Fernandez-Carasa, Irene, Berkowitz, Laura, Carballo Carbajal, Iria, Ezquerra Trabalón, Mario, Fernandez Santiago, Ruben, Kapahi, Pankaj, Raya Chamorro, Ángel, Miranda Vizuete, Antonio, Miguel Lizcano, Jose, Vila, Miquel, Caldwell, Kim A., Caldwell, Guy A., Consiglio, Antonella, Dalfo, Esther
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/172327
Acceso en línea:https://hdl.handle.net/2445/172327
Access Level:acceso abierto
Palabra clave:Malaltia de Parkinson
Malalties neurodegeneratives
Parkinson's disease
Neurodegenerative Diseases
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spelling The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced ToxicityKim, HannaCalatayud Aristoy, CarlesGuha, SanjibFernandez-Carasa, IreneBerkowitz, LauraCarballo Carbajal, IriaEzquerra Trabalón, MarioFernandez Santiago, RubenKapahi, PankajRaya Chamorro, ÁngelMiranda Vizuete, AntonioMiguel Lizcano, JoseVila, MiquelCaldwell, Kim A.Caldwell, Guy A.Consiglio, AntonellaDalfo, EstherMalaltia de ParkinsonMalalties neurodegenerativesParkinson's diseaseNeurodegenerative DiseasesParkinson's disease is associated with intracellular α-synuclein accumulation and ventral midbrain dopaminergic neuronal death in the Substantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has been suggested to participate to Parkinson's disease pathogenesis. Nevertheless, its exact contribution remains obscure. To unveil the participation of the Rho GTPase family to the molecular pathogenesis of Parkinson's disease, we first used C elegans to demonstrate the role of the small GTPase RAC1 (ced-10 in the worm) in maintaining dopaminergic function and survival in the presence of alpha-synuclein. In addition, ced-10 mutant worms determined an increase of alpha-synuclein inclusions in comparison to control worms as well as an increase in autophagic vesicles. We then used a human neuroblastoma cells (M17) stably over-expressing alpha-synuclein and found that RAC1 function decreased the amount of amyloidogenic alpha-synuclein. Further, by using dopaminergic neurons derived from patients of familial LRRK2-Parkinson's disease we report that human RAC1 activity is essential in the regulation of dopaminergic cell death, alpha-synuclein accumulation, participates in neurite arborization and modulates autophagy. Thus, we determined for the first time that RAC1/ced-10 participates in Parkinson's disease associated pathogenesis and established RAC1/ced-10 as a new candidate for further investigation of Parkinson's disease associated mechanisms, mainly focused on dopaminergic function and survival against α-synuclein-induced toxicity.Humana Press2020202020182020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion20 p.application/pdfhttps://hdl.handle.net/2445/172327Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1007/s12035-018-0881-7Molecular Neurobiology, 2018, vol. 55, num. 9, p. 7533-7552https://doi.org/10.1007/s12035-018-0881-7https://doi.org/10.1007/s12035-018-1010-3info:eu-repo/grantAgreement/EC/FP7/311736cc by (c) Kim at al., 2018http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1723272026-05-29T05:05:01Z
dc.title.none.fl_str_mv The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity
title The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity
spellingShingle The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity
Kim, Hanna
Malaltia de Parkinson
Malalties neurodegeneratives
Parkinson's disease
Neurodegenerative Diseases
title_short The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity
title_full The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity
title_fullStr The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity
title_full_unstemmed The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity
title_sort The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity
dc.creator.none.fl_str_mv Kim, Hanna
Calatayud Aristoy, Carles
Guha, Sanjib
Fernandez-Carasa, Irene
Berkowitz, Laura
Carballo Carbajal, Iria
Ezquerra Trabalón, Mario
Fernandez Santiago, Ruben
Kapahi, Pankaj
Raya Chamorro, Ángel
Miranda Vizuete, Antonio
Miguel Lizcano, Jose
Vila, Miquel
Caldwell, Kim A.
Caldwell, Guy A.
Consiglio, Antonella
Dalfo, Esther
author Kim, Hanna
author_facet Kim, Hanna
Calatayud Aristoy, Carles
Guha, Sanjib
Fernandez-Carasa, Irene
Berkowitz, Laura
Carballo Carbajal, Iria
Ezquerra Trabalón, Mario
Fernandez Santiago, Ruben
Kapahi, Pankaj
Raya Chamorro, Ángel
Miranda Vizuete, Antonio
Miguel Lizcano, Jose
Vila, Miquel
Caldwell, Kim A.
Caldwell, Guy A.
Consiglio, Antonella
Dalfo, Esther
author_role author
author2 Calatayud Aristoy, Carles
Guha, Sanjib
Fernandez-Carasa, Irene
Berkowitz, Laura
Carballo Carbajal, Iria
Ezquerra Trabalón, Mario
Fernandez Santiago, Ruben
Kapahi, Pankaj
Raya Chamorro, Ángel
Miranda Vizuete, Antonio
Miguel Lizcano, Jose
Vila, Miquel
Caldwell, Kim A.
Caldwell, Guy A.
Consiglio, Antonella
Dalfo, Esther
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malaltia de Parkinson
Malalties neurodegeneratives
Parkinson's disease
Neurodegenerative Diseases
topic Malaltia de Parkinson
Malalties neurodegeneratives
Parkinson's disease
Neurodegenerative Diseases
description Parkinson's disease is associated with intracellular α-synuclein accumulation and ventral midbrain dopaminergic neuronal death in the Substantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has been suggested to participate to Parkinson's disease pathogenesis. Nevertheless, its exact contribution remains obscure. To unveil the participation of the Rho GTPase family to the molecular pathogenesis of Parkinson's disease, we first used C elegans to demonstrate the role of the small GTPase RAC1 (ced-10 in the worm) in maintaining dopaminergic function and survival in the presence of alpha-synuclein. In addition, ced-10 mutant worms determined an increase of alpha-synuclein inclusions in comparison to control worms as well as an increase in autophagic vesicles. We then used a human neuroblastoma cells (M17) stably over-expressing alpha-synuclein and found that RAC1 function decreased the amount of amyloidogenic alpha-synuclein. Further, by using dopaminergic neurons derived from patients of familial LRRK2-Parkinson's disease we report that human RAC1 activity is essential in the regulation of dopaminergic cell death, alpha-synuclein accumulation, participates in neurite arborization and modulates autophagy. Thus, we determined for the first time that RAC1/ced-10 participates in Parkinson's disease associated pathogenesis and established RAC1/ced-10 as a new candidate for further investigation of Parkinson's disease associated mechanisms, mainly focused on dopaminergic function and survival against α-synuclein-induced toxicity.
publishDate 2018
dc.date.none.fl_str_mv 2018
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/172327
url https://hdl.handle.net/2445/172327
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1007/s12035-018-0881-7
Molecular Neurobiology, 2018, vol. 55, num. 9, p. 7533-7552
https://doi.org/10.1007/s12035-018-0881-7
https://doi.org/10.1007/s12035-018-1010-3
info:eu-repo/grantAgreement/EC/FP7/311736
dc.rights.none.fl_str_mv cc by (c) Kim at al., 2018
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Kim at al., 2018
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 20 p.
application/pdf
dc.publisher.none.fl_str_mv Humana Press
publisher.none.fl_str_mv Humana Press
dc.source.none.fl_str_mv Articles publicats en revistes (Patologia i Terapèutica Experimental)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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