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

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dc.contributor.authorKim, Hanna
dc.contributor.authorCalatayud, Caries
dc.contributor.authorGuha, Sanjib
dc.contributor.authorFernandez-Carasa, Irene
dc.contributor.authorBerkowitz, Laura
dc.contributor.authorCarballo-Carbajal, Iria
dc.contributor.authorEzquerra, Mario
dc.contributor.authorFernandez-Santiago, Ruben
dc.contributor.authorKapahi, Pankaj
dc.contributor.authorRaya, Angel
dc.contributor.authorMiranda-Vizuete, Antonio
dc.contributor.authorMiguel Lizcano, Jose
dc.contributor.authorVila, Miquel
dc.contributor.authorCaldwell, Kim A.
dc.contributor.authorCaldwell, Guy A.
dc.contributor.authorConsiglio, Antonella
dc.contributor.authorDalfo, Esther
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.contributor.otherInstitut d'Investigacio Biomedica de Bellvitge (IDIBELL)
dc.contributor.otherBellvitge University Hospital
dc.contributor.otherUniversity of Barcelona
dc.contributor.otherHospital Duran i Reynals
dc.contributor.otherCentro de Medicina Regenerativa de Barcelona
dc.contributor.otherBuck Institute for Research on Aging
dc.contributor.otherAutonomous University of Barcelona
dc.contributor.otherHospital Universitari Vall d'Hebron
dc.contributor.otherVall d'Hebron Institut de Recerca (VHIR)
dc.contributor.otherHospital Clinic de Barcelona
dc.contributor.otherIDIBAPS
dc.contributor.otherICREA
dc.contributor.otherConsejo Superior de Investigaciones Cientificas (CSIC)
dc.contributor.otherUniversity of Sevilla
dc.contributor.otherCSIC-JA-USE - Instituto de Biomedicina de Sevilla (IBIS)
dc.contributor.otherVirgen del Rocio University Hospital
dc.contributor.otherUniversitat de Vic - Universitat Central de Catalunya (UVic-UCC)
dc.date.accessioned2023-09-28T22:05:11Z
dc.date.available2023-09-28T22:05:11Z
dc.date.issued2018
dc.description.abstractParkinson's disease is associated with intracellular alpha-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 RACI (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 firm patients of familial LRRIC2-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 alpha-synuclein-induced toxicity.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationKim, 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, J. M., Vila, M., Caldwell, K. A., Caldwell, G. A., Consiglio, A., & Dalfo, E. (2018). The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against α-Synuclein-Induced Toxicity. In Molecular Neurobiology (Vol. 55, Issue 9, pp. 7533–7552). Springer Science and Business Media LLC. https://doi.org/10.1007/s12035-018-0881-7
dc.identifier.doi10.1007/s12035-018-0881-7
dc.identifier.orcidhttps://orcid.org/0000-0002-3988-6254
dc.identifier.orcidhttps://orcid.org/0000-0002-3154-5383
dc.identifier.orcidhttps://orcid.org/0000-0002-4403-8006
dc.identifier.orcidhttps://orcid.org/0000-0002-6856-5396
dc.identifier.orcidhttps://orcid.org/0000-0002-8195-3510
dc.identifier.orcidhttps://orcid.org/0000-0002-3988-6254
dc.identifier.orcidhttps://orcid.org/0000-0002-4582-0702
dc.identifier.orcidhttps://orcid.org/0000-0002-3154-5383
dc.identifier.orcidhttps://orcid.org/0000-0003-3246-6641
dc.identifier.orcidhttps://orcid.org/0000-0003-2189-9775
dc.identifier.orcidhttps://orcid.org/0000-0003-4677-8515
dc.identifier.orcidhttps://orcid.org/0000-0003-3246-6641
dc.identifier.orcidhttps://orcid.org/0000-0003-0032-4198
dc.identifier.orcidhttps://orcid.org/0000-0002-1352-989X
dc.identifier.orcidhttps://orcid.org/0000-0003-1362-371X
dc.identifier.urihttps://ir.ua.edu/handle/123456789/12322
dc.languageEnglish
dc.language.isoen_US
dc.publisherSpringer
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectParkinson's disease
dc.subjectDopaminergic neurons
dc.subjectAlpha-synuclein accumulation
dc.subjectAutophagy impairment
dc.subjectRAC1/ced-10
dc.subjectIN-VIVO
dc.subjectALZHEIMERS-DISEASE
dc.subjectSIGNALING PATHWAYS
dc.subjectAPOPTOTIC CELL
dc.subjectSTEM-CELLS
dc.subjectAUTOPHAGY
dc.subjectPROTEIN
dc.subjectGENE
dc.subjectDEGRADATION
dc.subjectLRRK2
dc.subjectNeurosciences
dc.titleThe Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicityen_US
dc.typeArticle
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