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

Parkinson's disease is associated with intracellular a-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 H, Calatayud C, Guha S, Fernández-Carasa I, Berkowitz L, Carballo-Carbajal I, Ezquerra M, Fernández-Santiago R, Kapahi P, Raya Á, Miranda-Vizuete A, Lizcano JM, Vila M, Caldwell KA, Caldwell GA, Consiglio A, Dalfo E
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p13624
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=13624
Access Level:acceso abierto
Palabra clave:Alpha-synuclein accumulation, Autophagy impairment, Dopaminergic neurons, Parkinson’s disease, RAC1/ced-10
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spelling The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.Kim HCalatayud CGuha SFernández-Carasa IBerkowitz LCarballo-Carbajal IEzquerra MFernández-Santiago RKapahi PRaya ÁMiranda-Vizuete ALizcano JMVila MCaldwell KACaldwell GAConsiglio ADalfo EAlpha-synuclein accumulation, Autophagy impairment, Dopaminergic neurons, Parkinson’s disease, RAC1/ced-10Parkinson's disease is associated with intracellular a-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 a-synuclein-induced toxicity.SPRINGER2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=13624MOLECULAR NEUROBIOLOGYISSN: 08937648ISSNe: 15591182reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p136242026-05-27T12:37:41Z
dc.title.none.fl_str_mv The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.
title The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.
spellingShingle The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.
Kim H
Alpha-synuclein accumulation, Autophagy impairment, Dopaminergic neurons, Parkinson’s disease, RAC1/ced-10
title_short The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.
title_full The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.
title_fullStr The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.
title_full_unstemmed The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.
title_sort The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.
dc.creator.none.fl_str_mv Kim H
Calatayud C
Guha S
Fernández-Carasa I
Berkowitz L
Carballo-Carbajal I
Ezquerra M
Fernández-Santiago R
Kapahi P
Raya Á
Miranda-Vizuete A
Lizcano JM
Vila M
Caldwell KA
Caldwell GA
Consiglio A
Dalfo E
author Kim H
author_facet Kim H
Calatayud C
Guha S
Fernández-Carasa I
Berkowitz L
Carballo-Carbajal I
Ezquerra M
Fernández-Santiago R
Kapahi P
Raya Á
Miranda-Vizuete A
Lizcano JM
Vila M
Caldwell KA
Caldwell GA
Consiglio A
Dalfo E
author_role author
author2 Calatayud C
Guha S
Fernández-Carasa I
Berkowitz L
Carballo-Carbajal I
Ezquerra M
Fernández-Santiago R
Kapahi P
Raya Á
Miranda-Vizuete A
Lizcano JM
Vila M
Caldwell KA
Caldwell GA
Consiglio A
Dalfo E
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alpha-synuclein accumulation, Autophagy impairment, Dopaminergic neurons, Parkinson’s disease, RAC1/ced-10
topic Alpha-synuclein accumulation, Autophagy impairment, Dopaminergic neurons, Parkinson’s disease, RAC1/ced-10
description Parkinson's disease is associated with intracellular a-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 a-synuclein-induced toxicity.
publishDate 2018
dc.date.none.fl_str_mv 2018
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://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=13624
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=13624
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv SPRINGER
publisher.none.fl_str_mv SPRINGER
dc.source.none.fl_str_mv MOLECULAR NEUROBIOLOGY
ISSN: 08937648
ISSNe: 15591182
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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