Differential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson’s disease

• Published in: NPJ Parkinson's Disease 2023-02, Vol.9 (1), p.15-15, Article 15
• Main Authors: Soto, Marta, Fernández, Manel, Bravo, Paloma, Lahoz, Sara, Garrido, Alicia, Sánchez-Rodríguez, Antonio, Rivera-Sánchez, María, Sierra, María, Melón, Paula, Roig-García, Ana, Naito, Anna, Casey, Bradford, Camps, Jordi, Tolosa, Eduardo, Martí, María-José, Infante, Jon, Ezquerra, Mario, Fernández-Santiago, Rubén
• Format: Article
• Language: English
• Subjects: 692/53; 692/53/2421; 692/617/375/1718; 692/699/375/346; 692/699/375/365; Biomarkers; Biomedical and Life Sciences; Biomedicine; MicroRNAs; Neurology; Neurosciences; Parkinson's disease
• ISSN: 2373-8057; 2373-8057
• DOI: 10.1038/s41531-023-00451-x

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.