Pathogenic mechanisms and potential therapeutic targets for Parkinson disease revealed by bioinformatic analysis of necroptosis and immune cell infiltration.

Abstract

Parkinson disease (PD) is an age-dependent neurodegenerative disease with very high prevalence by age 80 years. Necroptosis is a newly identified form of programmed cell death implicated in neurodegenerative diseases, but has not yet been conclusively associated with PD. This study examined the contributions of necroptosis to PD using bioinformatics analysis. Datasets GSE26927, GSE49036, and GSE54536 from the gene expression omnibus database were analyzed for differentially expressed genes (DEGs). These DEGs were then subjected to gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis to identify associated functions and signaling mechanisms. Necroptosis-related differentially expressed genes (NRDEGs) were then identified by the overlap of DEGs and the necroptosis gene set hsa04217. The STRING database and Cytoscape software were then used to build and visualize a protein-protein interaction network and identify hubs and key functional modules among NRDEGs. In addition, immune cell type abundance was analyzed based on DEGs using ImmuCellAI. The identified DEGs, KEGG pathway enrichment terms, and protein-protein interaction network structures of NRDEGs were validated using an independent dataset (GSE54536). The necroptosis pathway was significantly enriched and activated in PD samples. Thirteen NRDEGs were identified in the GSE26927 and GSE49036 datasets, including receptor interacting serine/threonine kinase 1, CASP8 and FADD like apoptosis regulator, TNFRSF1A associated via death domain, and interleukin 1 beta, of which 6 were validated in the GSE54536 dataset. According to gene ontology and KEGG analyses, these NRDEGs are involved in necroptosis-related processes, apoptosis, B cell receptor signaling pathways, and NOD-like receptor signaling pathways. Analysis of DEGs also revealed significant increases in CD8 + T cell and Tex cell infiltration and significant decreases in B cell and T gamma delta cell infiltration within the PD brain. Necroptosis pathways are active in PD and associated with immune cell infiltration. The factors controlling necroptotic signaling and immune infiltration identified in this study may be valuable diagnostic markers and therapeutic targets for PD.