Multi-omic landscaping of human midbrains identifies neuroinflammation as major disease mechanism in advanced-stage Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The disease mechanisms of sporadic PD are not yet completely understood. Therefore, causative therapies are still lacking. To obtain a more integrative view of disease-mediated alterations, we investigated the molecular landscape of PD in human post-mortem midbrains. Tissue from 13 PD patients and 10 controls was subjected to small RNA sequencing, transcriptomics, and proteomics analysis. Differential expression analyses were performed reveal multiple deregulated molecular targets linked to known pathomechanisms of PD as well as novel processes. We found significant differential expression of miR-539-3p, miR-376a-5p, miR-218-5p, and miR-369-3p, the valid miRNA-mRNA interacting pairs of miR-218-5p/RAB6C, and miR-369-3p/GTF2H3, as well as multiple proteins relevant in the pathology of PD, including CHI3L1, SELENBP1, PRDX1, HSPA1B, and TH. Vertical integration of multiple omics analyses allowed to validate disease-mediated molecular alterations across different molecular layers and functional annotation of differentially expressed targets identified a strong enrichment of pathways related to inflammation and activation of the immune response. This suggests that neuroinflammation may significantly contribute to disease progression in PD and may be a promising therapeutic target in advanced stages of PD.