In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson's disease

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dc.contributor.authorCortés, Adriana
dc.contributor.authorPhung, Toan K.
dc.contributor.authorMena, Lorena de
dc.contributor.authorGarrido, Alicia
dc.contributor.authorInfante, Jon
dc.contributor.authorRuíz-Martínez, Javier
dc.contributor.authorGalmés-Ordinas, Miquel À.
dc.contributor.authorGlendinning, Sophie
dc.contributor.authorPérez, Jesica
dc.contributor.authorRoig, Ana
dc.contributor.authorSoto, Marta
dc.contributor.authorCosgaya, Marina
dc.contributor.authorRavasi, Valeria
dc.contributor.authorFernández, Manel
dc.contributor.authorRubiano-Castro, Alejandro
dc.contributor.authorDíaz, Ramón
dc.contributor.authorHernández-Eguiazu, Haizea
dc.contributor.authorSánchez-Quintana, Coro
dc.contributor.authorVinagre-Aragón, Ana
dc.contributor.authorMondragón, Elisabet
dc.contributor.authorCroitoru, Ioana
dc.contributor.authorRivera-Sánchez, María
dc.contributor.authorCorrales-Pardo, Andrea
dc.contributor.authorSierra, María
dc.contributor.authorTolosa, Eduardo
dc.contributor.authorMalagelada, Cristina
dc.contributor.authorNirujogi, Raja S.
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorAlessi, Dario R.
dc.contributor.authorMartí, María J.
dc.contributor.authorEzquerra, Mario
dc.contributor.authorFernández-Santiago, Rubén
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2025-08-04T17:11:27Z
dc.date.available2025-08-04T17:11:27Z
dc.date.issued2024-12-20
dc.date.updated2025-08-04T16:59:24Z
dc.description.abstractLeucine-rich repeat kinase 2 (LRRK2) inhibition is a promising disease-modifying therapy for LRRK2-associated Parkinson's disease (L2PD) and idiopathic PD. However, pharmacodynamic readouts and progression biomarkers for clinical trials aiming for disease modification are insufficient, given that no endogenous marker reflecting enhanced kinase activity of the most common LRRK2 G2019S mutation has yet been reported in L2PD patients.Using phospho-/proteomic analyses, we assessed the impact of LRRK2-activating mutations in peripheral blood mononuclear cells from an LRRK2 clinical cohort from Spain (n = 174). The study groups encompassed G2019S L2PD patients (n = 37), non-manifesting LRRK2 mutation carriers of G2019S (here termed G2019S L2NMCs) (n = 27), R1441G L2PD patients (n = 14), R1441G L2NMCs (n = 11), idiopathic PD patients (n = 40) and healthy controls (n = 45).We identified 207 differentially regulated proteins in G2019S L2PD compared with controls (39 upregulated and 168 downregulated) and 67 in G2019S L2NMCs (10 upregulated and 57 downregulated). G2019S downregulated proteins affected the endolysosomal pathway, proteostasis and mitochondria, e.g. ATIC, RAB9A or LAMP1. At the phospho-proteome level, we observed increases in endogenous phosphorylation levels of pSer106 RAB12 in G2019S carriers, which were validated by immunoblotting after 1 year of follow-up (n = 48). Freshly collected peripheral blood mononuclear cells from three G2019S L2PD, one R1441G L2PD, one idiopathic PD and five controls (n = 10) showed strong diminishment of pSer106 RAB12 phosphorylation levels after in vitro administration of the MLi-2 LRRK2 inhibitor. Using machine learning, we identified an 18-feature G2019S phospho-/protein signature discriminating G2019S L2PD, L2NMCs and controls with 96% accuracy that was correlated with disease severity, i.e. UPDRS-III motor scoring.Using easily accessible peripheral blood mononuclear cells from a LRRK2 clinical cohort, we identified elevated levels of pSer106 RAB12 as an endogenous biomarker of G2019S carriers. Our data suggest that monitoring pSer106 RAB12 phosphorylation could be a relevant biomarker for tracking LRRK2 activation, particularly in G2019S carriers. Future work might determine whether pSer106 RAB12 could help with patient enrichment and monitoring drug efficacy in LRRK2 clinical trials. The LRRK2 activating mutation G2019S is the most frequent genetic cause of Parkinson's disease. Through phospho-proteome analysis of blood, Cort & eacute;s et al. identify elevated phospho-RAB12 levels as an endogenous biomarker of G2019S mutation carriers, with potential utility in clinical trials.en
dc.description.sponsorshipThis study was supported by a grant from the Michael J. Fox Foundation for Parkinson's Research (MJFF) (#MJFF-000858) to R.F.S., M.E., C.M., E.S., J.I. and J.R.M.
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/zip
dc.identifier.citationCortés, A., Phung, T. K., Mena, L. de, Garrido, A., Infante, J., Ruíz-Martínez, J., Galmés-Ordinas, M. Á., Glendinning, S., Pérez, J., Roig, A., Soto, M., Cosgaya, M., Ravasi, V., Fernández, M., Rubiano-Castro, A., Díaz, R., Hernández-Eguiazu, H., Sánchez-Quintana, C., Vinagre-Aragón, A., Mondragón, E., Croitoru, I., Rivera-Sánchez, M., Corrales-Pardo, A., Sierra, M., Tolosa, E., Malagelada, C., Nirujogi, R. S., Fernández-Irigoyen, J., Santamaría, E., Alessi, D. R., Martí, M. J., Ezquerra, M., Fernández-Santiago, R. (2025) In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson's disease. Brain, 148(6), 2075-2092. https://doi.org/10.1093/brain/awae404.
dc.identifier.doi10.1093/brain/awae404
dc.identifier.issn0006-8950
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/54584
dc.language.isoeng
dc.publisherOxford University Press
dc.relation.ispartofBrain 148(6), 2025, 2075-2092
dc.relation.publisherversionhttps://doi.org/10.1093/brain/awae404
dc.rights© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectParkinson's diseaseen
dc.subjectLeucine-rich repeat kinase 2en
dc.subjectPeripheral blood mononuclear cellsen
dc.subjectPhospho-/proteomicsen
dc.subjectNon-manifesting carriersen
dc.subjectBiomarkeren
dc.titleIn-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson's diseaseen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication.latestForDiscovery86d1b76e-4790-40b1-a3ec-72331c5c6199

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