Identification of a shared blood–brain transcriptomic signature in Parkinson’s disease using bioinformatic and network pharmacology approaches

Parkinsons disease, characterized by the aggregation of alpha-synuclein is a complex neurodegenerative disorder with the fastest global prevalence growth. The identification of shared genes expressed in both blood and brain of Parkinson's disease patients improves the knowledge on peripheral pathophysiology of the disease and facilitates identification of minimally invasive potential biomarkers from these shared genes. Our study intends to identify a shared transcriptomic signature between the blood and brain critical for developing minimally invasive biomarkers and understanding systemic disease progression. This study implemented an integrative bioinformatic approach towards the public microarray dataset comprising of both human Parkinson's disease blood and post-mortem brain cohorts. After routine data preparation and differential gene expression analysis across tissues, functional annotation, protein-protein interaction networks, and topological hub analysis were utilized to delineate underlying systemic pathways. A robust nine-gene signature-ANK1, CMAS, GUCY1B1, PRKAR2B, PSD3, RAB27B, SLC18A2, SNCA, and UCHL1-was downregulated in both blood and brain tissue, as demonstrated by the comparative gene expression analysis. Functional enrichment revealed a fundamental impairment in vesicle processing and synaptic maintenance, implying a failure in the cellular mechanisms necessary for neurotransmitter transport and the removal of protein aggregates-both of which play a crucial role in the neurodegenerative advancement of Parkinson's Disease. Non-compensated cellular homeostatic collapse indicated by concurrent decreases in RAB27B (vesicular clearance), UCHL1 (protein recycling), and SLC18A2 (synaptic transmission). NANOG, SNCA, UCHL1, SLC18A2, and ANK1 were found to be important regulatory hubs by topological analysis. This coordinated downregulation offers molecular evidence of an uncompensated systemic homeostatic failure in Parkinson's disease.