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bioRxiv · 10.1101/2025.04.15.648997

Cellular and Extracellular microRNA Dysregulation in LRRK2-Linked Parkinson's Disease

Knab, F.·Lee, J.-H.·Nirujogi, R.·Menden, K.·Busra Isik, F.·Rajkumar, A. P.·Czemmel, S.·Fitzgerald, J.·Gasser, T.
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Abstract

Background and objectiveThe discovery of cell-free micro-RNAs in body fluids has made them a promising biomarker target in the field of neurodegenerative diseases. Although they have been reported to be differentially expressed in biofluids and tissues from sporadic Parkinsons disease patients, it remains unclear whether similar observations can be made in patients with genetic forms of the disease and if miRNA profiles reflect mutation-specific pathogenic pathways. Since induced pluripotent stem cell-derived neurons represent a widely used research model for both sporadic and familial Parkinsons disease, we sought to assess the usability of this model for the identification of differentially expressed cell-free micro-RNAs in the context of the Parkinsons disease-related LRRK2 G2019S mutation in a proof-of-concept study. Materials and methodsWe isolated extracellular vesicles carrying cell-free RNA from patient-derived induced pluripotent stem cells carrying the LRRK2 G2019S mutation and their gene-corrected isogenic controls. After the generation of small-RNA libraries and differential expression analysis, we quantified expression levels of fourteen micro-RNAs in an independent batch of cell-free and cellular RNA via RT-qPCR. Finally, we quantified pRab10 levels as a proxy of LRRK2 activity and correlated observable changes to the miRNA expression levels. ResultsWe successfully isolated extracellular vesicles from induced pluripotent stem cell-derived human dopaminergic neurons. We detected over 2000 different micro-RNAs of which 56 were differentially expressed. Dysregulation of four micro-RNAs was confirmed in an independent batch of cell-free RNA. We discovered a high correlation between changes in the cell-free and cellular micro-RNAomes. Finally, we showed poor correlation between LRRK2 expression or activity and miRNA expression levels. ConclusionsOur results suggest that patients carrying the LRRK2 G2019S mutation display alterations in cellular and cell-free micro-RNA expression levels. Notably, the miRNA changes observed in this study did not follow a linear relationship with LRRK2 expression levels or kinase activity. Validation in larger cohorts will be necessary.

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Knab, F., Lee, J.-H., Nirujogi, R., Menden, K., Busra Isik, F., Rajkumar, A. P., Czemmel, S., Fitzgerald, J., Gasser, T.. 2025-04-20. Cellular and Extracellular microRNA Dysregulation in LRRK2-Linked Parkinson's Disease. https://doi.org/10.1101/2025.04.15.648997

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