npj Parkinson's Disease (Feb 2023)

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

  • Marta Soto,
  • Manel Fernández,
  • Paloma Bravo,
  • Sara Lahoz,
  • Alicia Garrido,
  • Antonio Sánchez-Rodríguez,
  • María Rivera-Sánchez,
  • María Sierra,
  • Paula Melón,
  • Ana Roig-García,
  • Anna Naito,
  • Bradford Casey,
  • Jordi Camps,
  • Eduardo Tolosa,
  • María-José Martí,
  • Jon Infante,
  • Mario Ezquerra,
  • Rubén Fernández-Santiago

DOI
https://doi.org/10.1038/s41531-023-00451-x
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 12

Abstract

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Abstract 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.