Using Extracellular miRNA Signatures to Identify Patients with LRRK2-Related Parkinson’s Disease

Background Mutations in the Leucine Rich Repeat Kinase 2 gene are highly relevant in both sporadic and familial cases of Parkinson’s disease. Specific therapies are entering clinical trials but patient stratification remains challenging. Dysregulated microRNA expression levels have been proposed as biomarker candidates in sporadic Parkinson’s disease. Objective In this proof-of concept study we evaluate the potential of extracellular miRNA signatures to identify LRRK2-driven molecular patterns in Parkinson’s disease. Methods We measured expression levels of 91 miRNAs via RT-qPCR in ten individuals with sporadic Parkinson’s disease, ten LRRK2 mutation carriers and eleven healthy controls using both plasma and cerebrospinal fluid. We compared miRNA signatures using heatmaps and t-tests. Next, we applied group sorting algorithms and tested sensitivity and specificity of their group predictions. Results miR-29c-3p was differentially expressed between LRRK2 mutation carriers and sporadic cases, with miR-425-5p trending towards significance. Individuals clustered in principal component analysis along mutation status. Group affiliation was predicted with high accuracy in the prediction models (sensitivity up to 89%, specificity up to 70%). miRs-128-3p, 29c-3p, 223-3p and 424-5p were identified as promising discriminators among all analyses. Conclusions LRRK2 mutation status impacts the extracellular miRNA signature measured in plasma and separates mutation carriers from sporadic Parkinson’s disease patients. Monitoring LRRK2 miRNA signatures could be an interesting approach to test drug efficacy of LRRK2-targeting therapies. In light of small sample size, the suggested approach needs to be validated in larger cohorts. ### Competing Interest Statement The authors have declared no competing interest. * CSF : Cerebrospinal fluid CtCSF : Ct values from CSF dataset Ctmultiplied : multiplied Ct values from CSF and plasma dataset Ctplasma : Ct values from plasma dataset Fc : Fold change GO : Gene Ontology HC : Healthy control LASSO : least absolute shrinkage and selection operator LEDD : levodopa equivalent daily dose Log2fc : log2(Fold change) LOOCV : Leave-One-Out Cross-Validation LRRK2 : Leucine-Rich Repeat Kinase 2 LRRK2MC : LRRK2 mutation carrier miRNA : microRNA MoCA : Montreal Cognitive Assessment PCA : Principal component analysis PD : Parkinson’s disease qPCR : real-time quantitative PCR RF : Random Forest RT : Reverse transcription sPD : sporadic PD UPDRS : Unified Parkinson Disease Rating Scale