{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T20:35:57Z","timestamp":1785875757030,"version":"3.56.0"},"reference-count":87,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson\u2019s Research","doi-asserted-by":"publisher","award":["#MJFF-000858"],"award-info":[{"award-number":["#MJFF-000858"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising disease-modifying therapy for LRRK2-associated Parkinson\u2019s 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.<\/jats:p>\n               <jats:p>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).<\/jats:p>\n               <jats:p>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.<\/jats:p>\n               <jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awae404","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T19:21:51Z","timestamp":1734722511000},"page":"2075-2092","source":"Crossref","is-referenced-by-count":9,"title":["In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson\u2019s disease"],"prefix":"10.1093","volume":"148","author":[{"given":"Adriana","family":"Cort\u00e9s","sequence":"first","affiliation":[{"name":"Proteored-ISCIII, Proteomics Platform, Clinical Neuroproteomics Unit, Navarrabiomed, Departamento de Salud, UPNA, IdiSNA , Pamplona ES 31008 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toan K","family":"Phung","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee , Dundee DD1 5EH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"de Mena","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Garrido","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Infante","sequence":"additional","affiliation":[{"name":"Neurology Service, University Hospital Marqu\u00e9s de Valdecilla-IDIVAL, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Santander ES 39008 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Ru\u00edz-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donostia University Hospital, Biogipuzkoa Health Research Institute, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , San Sebasti\u00e1n ES 20014 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miquel \u00c0","family":"Galm\u00e9s-Ordinas","sequence":"additional","affiliation":[{"name":"In Silico Medicinal Chemistry, Division of Cancer Therapeutics, The Institute of Cancer Research , London SW7 3RP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Glendinning","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee , Dundee DD1 5EH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesica","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Roig","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Soto","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Cosgaya","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 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Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Rubiano-Castro","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3n","family":"D\u00edaz","sequence":"additional","affiliation":[{"name":"Proteored-ISCIII, Proteomics Platform, Clinical Neuroproteomics Unit, Navarrabiomed, Departamento de Salud, UPNA, IdiSNA , Pamplona ES 31008 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haizea","family":"Hern\u00e1ndez-Eguiazu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donostia University Hospital, Biogipuzkoa Health Research Institute, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , San Sebasti\u00e1n ES 20014 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coro","family":"S\u00e1nchez-Quintana","sequence":"additional","affiliation":[{"name":"Neurology Service, University Hospital Marqu\u00e9s de Valdecilla-IDIVAL, Centro de Investigaci\u00f3n Biom\u00e9dica en 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Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7185-436X","authenticated-orcid":false,"given":"Cristina","family":"Malagelada","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Faculty of Medicine, Universitat de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja S","family":"Nirujogi","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee , Dundee DD1 5EH 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J","family":"Mart\u00ed","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3246-6641","authenticated-orcid":false,"given":"Mario","family":"Ezquerra","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4582-0702","authenticated-orcid":false,"given":"Rub\u00e9n","family":"Fern\u00e1ndez-Santiago","sequence":"additional","affiliation":[{"name":"Lab for Parkinson\u2019s & Other Movement Disorders, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Service, Hospital Cl\u00ednic de Barcelona, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) CB06\/05\/0018-ISCIII , Barcelona ES 08036 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