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 characterised 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 2,604 PPMI participants (Healthy n = 658; PD n = 1,946), stratified into pre-clinical (n = 561), mild, moderate, and severe stages. Differential expression (adjusted p < 0.05; |fold change| > 1.5) revealed a U-shaped trajectory, with maximal alterations in pre-clinical (7,427 DEGs; 157 DE-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 252 miRNA–mRNA pairs, driven by hub miRNAs including miR-34a-5p, miR-1299, miR-3120-5p, and miR-412-3p. Using pre-clinical DE-miRNAs for classification (n = 1,219), Naive Bayes and GLMNet achieved AUCs of 0.886 and 0.883 with minimal overfitting. Taken together, these findings highlight the possible employment of early spliceosomal dysfunction and miRNA-mediated regulation as novel blood-based biomarkers of pre-clinical PD.