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This 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.

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Cortés, AdrianaAuthorDe Mena, LorenaAuthorPerez, JesicaAuthorRavasi, ValeriaAuthorRubiano-Castro, AlejandroAuthorTolosa, EduardoAuthorEzquerra, MarioCorresponding AuthorFernandez-Santiago, RubenCorresponding Author

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Early Access

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

Publicated to:Brain. - 2025-04-08 (), DOI: 10.1093/brain/awae404

Authors: Cortes, Adriana; Phung, Toan K; de Mena, Lorena; Garrido, Alicia; Infante, Jon; Ruiz-Martinez, Javier; Galmes-Ordinas, Miquel a; Glendinning, Sophie; Perez, Jesica; Roig, Ana; Soto, Marta; Cosgaya, Marina; Ravasi, Valeria; Fernandez, Manel; Rubiano-Castro, Alejandro; Diaz, Ramon; Sanchez-Quintana, Coro; Vinagre-Aragon, Ana; Mondragon, Elisabet; Croitoru, Ioana; Rivera-Sanchez, Maria; Corrales-Pardo, Andrea; Sierra, Maria; Tolosa, Eduardo; Malagelada, Cristina; Nirujogi, Raja S; Fernandez-Irigoyen, Joaquin; Santamaria, Enrique; Alessi, Dario R; Marti, Maria J; Ezquerra, Mario; Fernandez-Santiago, Ruben

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Abstract

Leucine-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.

Keywords

AutophagyBiomarkeBiomarkerCyclohydrolaseEndolysosomal systemHeterogeneityIdentificationLeucine-rich repeat kinase 2Leucine-rich repeat kinase 2 (lrrk2)Lrrk2 g2019sMechanismNon-manifesting carriersParkinson's diseaseParkinson’s disease (pd)PenetrancePeripheral blood mononuclear cellsPeripheral blood mononuclear cells (pbmcs)Phospho-/proteomicsProteiR1441g mutation

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Brain due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2025, it was in position 11/310, thus managing to position itself as a Q1 (Primer Cuartil), in the category Neurosciences. Notably, the journal is positioned above the 90th percentile.

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-03:

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 12.6.
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United Kingdom.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Cortes Brioso, Abel) and Last Author (Fernandez Santiago, Ruben).

the authors responsible for correspondence tasks have been Ezquerra Trabalón, Mario Antonio and Fernandez Santiago, Ruben.