Extracellular vesicle microRNAs from iPSC-derived dopaminergic neurons as biomarkers in Prion and Parkinson’s Diseases.

Prion diseases (PrD) and Parkinson’s disease (PD) are neurodegenerative disorders characterized by protein misfolding, neuroinflammation, and progressive neuronal loss. Identifying molecular markers involved in these shared pathological mechanisms remains a major challenge. MicroRNAs (miRNAs), especially those carried by extracellular vesicles (EVs), have emerged as important mediators of intercellular communication and as potential biomarkers of neurodegeneration. In this study, we experimentally characterized miRNAs enriched in EVs secreted during the dopaminergic differentiation of neural precursors derived from human induced pluripotent stem cells (iPSCs). Among the differentially expressed miRNAs, miR-21-5p, miR-9-5p, and miR-218-5p were prominent for their known involvement in neuroinflammatory and apoptotic pathways previously associated with prion diseases. These miRNAs regulate key processes such as synaptic signaling, neuronal survival, and immune modulation, which are commonly disrupted in both PrD and PD. Furthermore, the high expression of miR-26a-5p, miR-24-3p, and miR-137 found provides new evidence that strengthens their relationship with these neurodegenerative processes. Our findings highlight the relevance of EV-associated miRNAs from iPSC-derived neurons as molecular signatures of neurodegeneration, reinforcing their potential use as biomarkers and therapeutic targets in prion-related diseases.