Single nucleus RNA sequencing profile analysis to reveal cell type specific common molecular drivers of Parkinson's disease and therapeutic agents.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, characterized by progressive motor and cognitive decline, leading to long-term disability and significantly impacting quality of life. While PD research has traditionally focused on dopaminergic neurons in the substantia nigra (SN), emerging evidence also suggests glial involvement in disease progression. So, this study explored PD-associated key genes from neuronal and glial cell types to uncover pathogenetic mechanisms and potential therapeutics by employing single-nucleus RNA sequencing (snRNA-seq) data from the accession number GSE184950. A total of 426,886 nuclei were analyzed, yielding 129,473 high-quality nuclei. Through rigorous quality control, clustering, and marker gene analysis using scVI and Scanpy, nine distinct cell types were delineated, including neurons, astrocytes, and microglia. 18 common differentially expressed genes (cDEGs) were identified across neuronal and glial cell types. Gene ontology (GO) and KEGG enrichment analyses revealed key terms associated with neurodegeneration, including PD. A total of six critical KGs, including HSPA1A, DNAJB1, BAG3, SYN1, CALB2, and NEFL, along with their key regulators, were identified by the protein-protein interaction network. Finally, three repurposed drugs (Celastrol, Withaferin-A, and Apomorphine) were suggested as the therapeutics agents for PD by molecular docking. In-silico ADME/T analyses were conducted using pkCSM and SwissADME to evaluate the pharmacokinetic properties of these compounds. These findings could shed light on PD mechanisms and hold promise for advancing diagnostics and therapies.