Converging peripheral blood microRNA profiles in Parkinson's disease and progressive supranuclear palsy
MicroRNAs regulate gene expression by suppressing messenger RNA translation and reflect epigenetic changes underlying cellular dysfunction in disease. To investigate microRNA dysregulation in neurodegeneration, we conducted a cross-sectional expression analysis in idiopathic Parkinson’s disease (PD; n = 367), progressive supranuclear palsy (PSP; n = 35), and healthy controls (n = 416) from the Luxembourg Parkinson’s Study. Analyses included prediction modeling, pathway enrichment, and target simulation of dysregulated microRNAs using probabilistic Boolean modeling. We identified 46 dysregulated microRNAs in PD versus controls and 16 in PSP versus controls, with four microRNAs overlapping between diseases. MicroRNA-based classifiers showed modest performance in distinguishing PD (maximum cross-validated AUC = 0.76) and PSP (AUC = 0.86) from controls, and limited accuracy for differentiating PSP from PD (AUC = 0.63). Pathway enrichment analysis revealed dysregulation of the natural killer cell pathway in both PD and PSP, suggesting a shared role of immune mechanisms. Probabilistic Boolean modeling demonstrated partially overlapping pathway disturbances in PD and PSP, including transcription factor EB activity, endoplasmic reticulum stress signaling, calcium signaling, dopaminergic transcription, and peroxisome proliferator-activated receptor gamma coactivator-1α activity, although mediated by distinct molecular mechanisms. Overall, these findings indicate partially convergent cellular dysfunction in PD and PSP, with overlapping downstream effects but disease-specific regulatory mechanisms.
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