Spatial transcriptome analysis of myenteric plexus and intestinal epithelium of colon in patients with Parkinson’s disease

Abstract Alpha-synuclein (AS) accumulation is found in the nerve plexuses of the gastrointestinal tract in patients with Parknison’s disease (PD). Moreover, alterations in microbiome composition and its metabolites were confirmed in the colon of patients with PD. However, there has been no study that evaluates transcriptomic alterations of the nerve plexus and intestinal epithelium simultaneously using in vivo tissue of patients with PD. Therefore, we aimed to investigate the gene expression profiles of the myenteric plexus and intestinal epithelium of the colon of patients with PD. Ten full-depth slides of paraffin-embedded surgical specimens of the colon or rectum from five patients with PD and five controls were included. AS accumulation was found in the myenteric plexus in all patients with PD. We performed spatial-specific transcriptomic profiling of the myenteric plexus and epithelium using the GeoMX Digital Spatial Profiler. Forty-one differentially expressed genes (DEGs) (36 up-regulated and 5 down-regulated) were identified in the myenteric plexus of patients with PD compared to controls. In the intestinal epithelium, 240 DEGs (81 up-regulated and 159 down-regulated) were identified. Pathway analysis showed upregulated response to type II interferon and lymphocyte activation, while downregulated cellular response to zinc and copper ions in the intestinal epithelium of patients with PD. In the myenteric plexus, neuroepithelial cell differentiation and axon development were upregulated. Network analysis showed the following key genes: and HLA-DRA, SERPINA1, and metallothioneins in the intestinal epithelium, and LAMP1, TUBB2A, and S100B in the myenteric plexus. This study suggests that inflammatory processes may occur in the intestinal epithelium, while neuronal regeneration mechanisms may be active in the myenteric plexus in patients with overtly developed PD. A spatial transcriptomic analysis of the brain and the gastrointestinal tract will enable a better understanding of the gut-brain axis in PD.