Sex-specific microRNA regulators of Parkinson disease: insights from cohort-stratified simulations of compensatory pathway dynamics

Parkinsons disease (PD) exhibits sex differences in prevalence, symptom severity, and progression, suggesting distinct underlying molecular mechanisms. However, the pathophysiological mechanisms remain largely obscure, particularly in the context of the post-transcriptional regulations, where microRNAs (miRNAs) suppress the expression of multiple genes. Bulk transcriptomic data often blur these effects, especially when regulatory patterns vary by sex or cell type. miRNAs have emerged as key regulators of PD-related processes, but their complexity demands computational methods that enable capturing the functional impact at the pathway level. In this study, we investigated how sex may affect miRNA-regulated PD pathways using Boolean modeling across two large PD cohorts, the Parkinsons Progression Markers Initiative (PPMI) and the Luxembourg Parkinsons Study (LuxPark). First, differential expression analysis identified significant variations in miRNA expression between the sexes across both cohorts. These miRNAs were analysed to identify molecular pathways that are over-represented among the predicted targets of the dysregulated microRNAs (i.e. enrichment analysis). The enriched pathways were used to build Boolean models to simulate the effects of sex-specific miRNA dysregulation. These simulations showed consistent male-specific impairment in mitochondrial biogenesis, and respiratory chain activity. Mitophagy and oxidative stress response pathways were also disrupted, alongside dysregulation of autophagy-related protein-folding mechanisms. Our findings suggest that sex-specific miRNA dysregulation contributes to differences in molecular patterns in PD by influencing compensatory related pathways and responses. These results highlight the need for sex-stratified approaches in modeling, translational research, and precision medicine strategies for disease-modifying treatments.