RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits

Mutations in the LRRK2 kinase are the most common cause of familial Parkinson's disease, and variants increase risk for the sporadic form of the disease. LRRK2 phosphorylates multiple RAB GTPases including RAB8A and RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which...

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Autores: Lara Ordóñez, Antonio J., Fernández, B., Fdez, Elena, Romo-Lozano, M., Madero-Pérez, J., Lobbestael, E., Baekelandt, Veerle, Aiastui, Ana, López de Munain, Adolfo, Melrose, H.L., Civiero, L., Hilfiker, Sabine
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/212719
Acceso en línea:http://hdl.handle.net/10261/212719
Access Level:acceso abierto
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spelling RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficitsLara Ordóñez, Antonio J.Fernández, B.Fdez, ElenaRomo-Lozano, M.Madero-Pérez, J.Lobbestael, E.Baekelandt, VeerleAiastui, AnaLópez de Munain, AdolfoMelrose, H.L.Civiero, L.Hilfiker, SabineMutations in the LRRK2 kinase are the most common cause of familial Parkinson's disease, and variants increase risk for the sporadic form of the disease. LRRK2 phosphorylates multiple RAB GTPases including RAB8A and RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which may interfere with ciliogenesis in a disease-relevant context. Our previous studies indicate that the centrosomal accumulation of phosphorylated RAB8A causes centrosomal cohesion deficits in dividing cells, including in peripheral patient-derived cells. Here, we show that both RAB8 and RAB10 contribute to the centrosomal cohesion deficits. Pathogenic LRRK2 causes the centrosomal accumulation not only of phosho-RAB8 but also of phospho-RAB10, and the effects on centrosomal cohesion are dependent on RAB8, RAB10 and RILPL1. Conversely, the pathogenic LRRK2-mediated ciliogenesis defects correlate with the centrosomal accumulation of both phospho-RAB8 and phospho-RAB10. LRRK2-mediated centrosomal cohesion and ciliogenesis alterations are observed in patient-derived peripheral cells, as well as in primary astrocytes from mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibition. These data suggest that the LRRK2-mediated centrosomal cohesion and ciliogenesis defects are distinct cellular readouts of the same underlying phospho-RAB8/RAB10/RILPL1 nexus and highlight the possibility that either centrosomal cohesion and/or ciliogenesis alterations may serve as cellular biomarkers for LRRK2-related PD.Michael J. Fox Foundation for Parkinson’s research (to S.H.); European Regional Development Fund; Spanish Ministry of Economy and Competitiveness (SAF2017-89402-R to S.H.); Spanish Ministry of Education, Culture and Sport (FPU15/05233 to A.J.L.O.).Oxford University PressMichael J. Fox Foundation for Parkinson's ResearchEuropean CommissionMinisterio de Economía y Competitividad (España)Ministerio de Educación, Cultura y Deporte (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/212719reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-89402-Rhttp://dx.doi.org/10.1093/hmg/ddz201Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2127192026-05-22T06:33:51Z
dc.title.none.fl_str_mv RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits
title RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits
spellingShingle RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits
Lara Ordóñez, Antonio J.
title_short RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits
title_full RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits
title_fullStr RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits
title_full_unstemmed RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits
title_sort RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits
dc.creator.none.fl_str_mv Lara Ordóñez, Antonio J.
Fernández, B.
Fdez, Elena
Romo-Lozano, M.
Madero-Pérez, J.
Lobbestael, E.
Baekelandt, Veerle
Aiastui, Ana
López de Munain, Adolfo
Melrose, H.L.
Civiero, L.
Hilfiker, Sabine
author Lara Ordóñez, Antonio J.
author_facet Lara Ordóñez, Antonio J.
Fernández, B.
Fdez, Elena
Romo-Lozano, M.
Madero-Pérez, J.
Lobbestael, E.
Baekelandt, Veerle
Aiastui, Ana
López de Munain, Adolfo
Melrose, H.L.
Civiero, L.
Hilfiker, Sabine
author_role author
author2 Fernández, B.
Fdez, Elena
Romo-Lozano, M.
Madero-Pérez, J.
Lobbestael, E.
Baekelandt, Veerle
Aiastui, Ana
López de Munain, Adolfo
Melrose, H.L.
Civiero, L.
Hilfiker, Sabine
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Michael J. Fox Foundation for Parkinson's Research
European Commission
Ministerio de Economía y Competitividad (España)
Ministerio de Educación, Cultura y Deporte (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Mutations in the LRRK2 kinase are the most common cause of familial Parkinson's disease, and variants increase risk for the sporadic form of the disease. LRRK2 phosphorylates multiple RAB GTPases including RAB8A and RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which may interfere with ciliogenesis in a disease-relevant context. Our previous studies indicate that the centrosomal accumulation of phosphorylated RAB8A causes centrosomal cohesion deficits in dividing cells, including in peripheral patient-derived cells. Here, we show that both RAB8 and RAB10 contribute to the centrosomal cohesion deficits. Pathogenic LRRK2 causes the centrosomal accumulation not only of phosho-RAB8 but also of phospho-RAB10, and the effects on centrosomal cohesion are dependent on RAB8, RAB10 and RILPL1. Conversely, the pathogenic LRRK2-mediated ciliogenesis defects correlate with the centrosomal accumulation of both phospho-RAB8 and phospho-RAB10. LRRK2-mediated centrosomal cohesion and ciliogenesis alterations are observed in patient-derived peripheral cells, as well as in primary astrocytes from mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibition. These data suggest that the LRRK2-mediated centrosomal cohesion and ciliogenesis defects are distinct cellular readouts of the same underlying phospho-RAB8/RAB10/RILPL1 nexus and highlight the possibility that either centrosomal cohesion and/or ciliogenesis alterations may serve as cellular biomarkers for LRRK2-related PD.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/212719
url http://hdl.handle.net/10261/212719
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-89402-R
http://dx.doi.org/10.1093/hmg/ddz201
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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