Druggable targets for Parkinson’s disease: transcriptomics based Mendelian randomization study

Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Currently available drugs for PD, can only relieve the symptoms of PD, but cannot prevent the progression of the disease and have serious side effects. Other new druggable therapeutic targets for PD are needed. First, six GEO datasets with transcriptomic data from the substantia nigra (SN) region of the brain were downloaded to find dysregulated druggable genes in PD. Then, Mendelian randomization (MR) and summary statistics-based MR (SMR) analysis were conducted using eQTL data from both brain tissue and blood to investigate the relationship between gene expression and PD. Next, the association between the expression of candidate druggable targets and disease stage was validated in an additional dataset GSE49036. Finally, a phenome-wide MR analysis was carried out to investigate the potential impact of candidate druggable genes on several other complex diseases or traits. Our study revealed 313 differentially expressed genes that may be directly targetable and have an impact on PD (FDR-p < 0.1). Through MR and SMR analysis, P2RX7 and RNASET2 were identified as feasible PD therapeutic targets, which were highly expressed in PD tissues and increased as the Braak stages increased. Phenome-wide MR analysis revealed other effects of targeting RNASET2. This study presents genetic support for the potential therapeutic properties of targeting P2RX7 and RNASET2, which will be useful for developing druggable therapeutic targets for PD.