Integrative blood transcriptomics identifies U1-snRNP gene repression and miRNA–mRNA regulatory hubs in pre-clinical Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of intraneuronal misfolded α-synuclein aggregates. Despite advances in understanding the underlying molecular mechanisms of PD, diagnosis still relies largely on clinical symptoms that appear relatively late in disease progression. To advance both the mechanistic understanding of PD and the development of new diagnostic tools, we here performed an integrative analysis of matched whole-blood mRNA-seq and miRNA-seq data from 2604 participants (Healthy n = 658; PD n = 1946) of the Parkinson’s Progression Markers Initiative (PPMI), stratified into pre-clinical ( n = 561), mild, moderate, and severe stages. Differential expression (adjusted p < 0.05; |fold change|> 0.58) revealed maximal alterations in pre-clinical (7386 differentially expressed genes; 156 differentially expressed miRNAs) and severe PD. Pre-clinical signatures were dominated by widespread downregulation, notably involving multiple U1 snRNA genes, indicating early repression of U1-snRNP spliceosomal components. Integration of predicted targets with Spearman anti-correlation identified 251 miRNA–mRNA pairs, driven by hub miRNAs including miR-34a-5p, miR-1299, miR-3120-5p, and miR-412-3p.Taken together, these findings highlight the importance of early spliceosomal dysfunction and miRNA dysregulation in preclinical PD, supporting their potential as novel blood-based biomarkers.