Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation
dc.contributor.author | Madero-Pérez, Jesús | |
dc.contributor.author | Fernández, Elena | |
dc.contributor.author | Fernández, Belén | |
dc.contributor.author | Lara Ordóñez, Antonio J. | |
dc.contributor.author | Ramírez, Marian Blanca | |
dc.contributor.author | Gómez-Suaga, Patricia | |
dc.contributor.author | Waschbüsch, Dieter | |
dc.contributor.author | Lobbestael, Evy | |
dc.contributor.author | Baekelandt, Veerle | |
dc.contributor.author | Nairn, Angus C. | |
dc.contributor.author | Ruiz-Martínez, Javier | |
dc.contributor.author | Aiastui, Ana | |
dc.contributor.author | López de Munain Arregui, Adolfo José | |
dc.contributor.author | Lis, Pawel | |
dc.contributor.author | Comptdaer, Thomas | |
dc.contributor.author | Taymans, Jean-Marc | |
dc.contributor.author | Chartier-Harlin, Marie-Christine | |
dc.contributor.author | Beilina, Alexandria | |
dc.contributor.author | Gonnelli, Adriano | |
dc.contributor.author | Cookson, Mark R. | |
dc.contributor.author | Greggio, Elisa | |
dc.contributor.author | Hilfiker, Sabine | |
dc.date.accessioned | 2019-04-05T07:35:42Z | |
dc.date.available | 2019-04-05T07:35:42Z | |
dc.date.issued | 2019-01-23 | |
dc.identifier.citation | Molecular Neurodegeneration 13 : (2019) // Article ID 3 | es_ES |
dc.identifier.issn | 1750-1326 | |
dc.identifier.uri | http://hdl.handle.net/10810/32346 | |
dc.description.abstract | Background: Mutations in LRRK2 are a common genetic cause of Parkinson's disease (PD). LRRK2 interacts with and phosphorylates a subset of Rab proteins including Rab8a, a protein which has been implicated in various centrosome-related events. However, the cellular consequences of such phosphorylation remain elusive. Methods: Human neuroblastoma SH-SY5Y cells stably expressing wildtype or pathogenic LRRK2 were used to test for polarity defects in the context of centrosomal positioning. Centrosomal cohesion deficits were analyzed from transiently transfected HEK293T cells, as well as from two distinct peripheral cell types derived from LRRK2-PD patients. Kinase assays, coimmunoprecipitation and GTP binding/retention assays were used to address Rab8a phosphorylation by LRRK2 and its effects in vitro. Transient transfections and siRNA experiments were performed to probe for the implication of Rab8a and its phosphorylated form in the centrosomal deficits caused by pathogenic LRRK2. Results: Here, we show that pathogenic LRRK2 causes deficits in centrosomal positioning with effects on neurite outgrowth, cell polarization and directed migration. Pathogenic LRRK2 also causes deficits in centrosome cohesion which can be detected in peripheral cells derived from LRRK2-PD patients as compared to healthy controls, and which are reversed upon LRRK2 kinase inhibition. The centrosomal cohesion and polarity deficits can be mimicked when co-expressing wildtype LRRK2 with wildtype but not phospho-deficient Rab8a. The centrosomal defects induced by pathogenic LRRK2 are associated with a kinase activity-dependent increase in the centrosomal localization of phosphorylated Rab8a, and are prominently reduced upon RNAi of Rab8a. Conclusions: Our findings reveal a new function of LRRK2 mediated by Rab8a phosphorylation and related to various centrosomal defects. Palabras clave | es_ES |
dc.description.sponsorship | S.H. was supported by the Michael J. Fox Foundation, the BBVA Foundation, FEDER, and the Spanish Ministry of Economy and Competitiveness (SAF2014-58653-R). E.G. was funded by the Michael J. Fox Foundation. J-M.T. and M.-C. C.-H. were funded by the Michael J. Fox Foundation, and M.-C. C.-H. was supported by Inserm, CHU de Lille, Lille University and the Ministere de la Recherche et de la Sante (PHRC Convergence). We gratefully acknowledge funding from the European Union's Horizon 2020 research and innovation programme (Marie Sklodowska-Curie Action Individual Fellowship to J.-M.T.). A.C.N. was supported by the Dept. of the Army (USAMRAA W23RYX-9049-N610) and NIH (DA10044). This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (to M.R.C.). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Biomed Central | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/SAF2014-58653-R | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | centrosome | es_ES |
dc.subject | LRRK2 | es_ES |
dc.subject | Parkinson's disease | es_ES |
dc.subject | phosphorylation | es_ES |
dc.subject | rab8a | es_ES |
dc.subject | cytoplasmic localization | es_ES |
dc.subject | G2019S mutation | es_ES |
dc.subject | cell-migration | es_ES |
dc.subject | 14-3-3 binding | es_ES |
dc.subject | kinase | es_ES |
dc.subject | trafficking | es_ES |
dc.subject | inhibitor | es_ES |
dc.subject | proteins | es_ES |
dc.subject | actin | es_ES |
dc.subject | golgi | es_ES |
dc.title | Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. | es_ES |
dc.rights.holder | Atribución 3.0 España | * |
dc.relation.publisherversion | https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-018-0235-y | es_ES |
dc.identifier.doi | 10.1186/s13024-018-0235-y | |
dc.contributor.funder | European Commission | |
dc.departamentoes | Neurociencias | es_ES |
dc.departamentoeu | Neurozientziak | es_ES |
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