biostudies-literatureSoto MGeneralitat de CatalunyaMinistry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministerio de Economía, Industria y Competitividad)Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)Ministry of Economy and Competitiveness | Instituto de Salud Carlos IIIMinisterio de Economía, Industria y Competitividad, Gobierno de EspañaGeneralitat de Catalunya (Government of Catalonia)Ministry of Economy and Competitiveness | Agencia Estatal de InvestigaciónMinistry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)Michael J. Fox Foundation for Parkinson’s Research15https://www.ebi.ac.uk/biostudies/studies/S-EPMC9894906biostudies-literatureUnknown9(1)The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson's disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years. Our cohort consisted of G2019S L2NMC stratified by dopamine transporter single-photon emission computed tomography (DaT-SPECT) into DaT-negative (n = 20) and DaT-positive L2NMC (n = 20), pheno-converted G2019S L2PD patients (n = 20), idiopathic PD (iPD) (n = 19), and controls (n = 40). We also screened a second cohort of L2PD patients (n = 19) and controls (n = 20) (Total n = 158). Compared to healthy controls, we identified eight deregulated miRNAs in DaT-negative L2NMC, six in DaT-positive L2NMC, and one in L2PD. Between groups, the highest miRNA differences, 24 candidate miRNAs, occurred between DaT-positive L2NMC and L2PD. Longitudinally, we found 11 common miRNAs with sustained variation in DaT-negative and DaT-positive L2NMCs compared to their baselines. Our study identifies novel miRNA alterations in premotor stages of PD co-occurring with progressive DaT-SPECT decline before motor manifestation, whose deregulation seems to attenuate after the diagnosis of L2PD. Moreover, we identified four miRNAs with relatively high discriminative ability (AUC = 0.82) between non-pheno-converted DaT-positive G2019S carriers and pheno-converted L2PD patients (miR-4505, miR-8069, miR-6125, and miR-451a), which hold potential as early progression biomarkers for PD.NPJ Parkinson's diseaseDifferential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson's disease.PMC9894906#SAF2015-73508-JIN#CPII18/00026AGAUR#2017SGR1502#CP19/00048#11849#FI21/00104#MDM-2017-0729CB06/05/0018-ISCIII#FI18/00221#FIS20-PI20/00659Casey BCamps JFernandez MTolosa EInfante JGarrido ASanchez-Rodriguez ARoig-Garcia ABravo PSoto MFernandez-Santiago RRivera-Sanchez MNaito AMarti MJEzquerra MSierra MLahoz SMelon PfalseDifferential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson's disease.The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson's disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years. Our cohort consisted of G2019S L2NMC stratified by dopamine transporter single-photon emission computed tomography (DaT-SPECT) into DaT-negative (n = 20) and DaT-positive L2NMC (n = 20), pheno-converted G2019S L2PD patients (n = 20), idiopathic PD (iPD) (n = 19), and controls (n = 40). We also screened a second cohort of L2PD patients (n = 19) and controls (n = 20) (Total n = 158). Compared to healthy controls, we identified eight deregulated miRNAs in DaT-negative L2NMC, six in DaT-positive L2NMC, and one in L2PD. Between groups, the highest miRNA differences, 24 candidate miRNAs, occurred between DaT-positive L2NMC and L2PD. Longitudinally, we found 11 common miRNAs with sustained variation in DaT-negative and DaT-positive L2NMCs compared to their baselines. Our study identifies novel miRNA alterations in premotor stages of PD co-occurring with progressive DaT-SPECT decline before motor manifestation, whose deregulation seems to attenuate after the diagnosis of L2PD. Moreover, we identified four miRNAs with relatively high discriminative ability (AUC = 0.82) between non-pheno-converted DaT-positive G2019S carriers and pheno-converted L2PD patients (miR-4505, miR-8069, miR-6125, and miR-451a), which hold potential as early progression biomarkers for PD.2023-01-01T00:00:00Z2023 Feb2026-03-17T15:43:41.2Z2025-04-06T14:06:04.49ZS-EPMC98949063673251410.1038/s41531-023-00451-x