Distinct Patterns of Gene Expression Changes in the Colon and Striatum of Young Mice Overexpressing Alpha-Synuclein Support Parkinson’s Disease as a Multi-System Process

Background: Evidence supports a role for the gut-brain axis in Parkinson’s disease (PD). Mice overexpressing human wild type α– synuclein (Thy1-haSyn) exhibit slow colonic transit prior to motor deficits, mirroring prodromal constipation PD. Identifying molecular changes gut could provide both biomarkers early diagnosis and gut-targeted therapies prevent progression. Objective: To identify Thy1-haSyn mice through gene expression profiling. Methods: Gene profiling was performed on (colon) brain (striatal) tissue from wild-type (WT) aged 1 3 months using 3′ RNA sequencing. Analysis included differential expression, set enrichment weighted co-expression network analysis (WGCNA). Results: At one month, (Thy1-haSyn vs. WT) of mitochondrial genes pathways related PD discordant between brain, with negative (enriched but positive gut. Linear regression WGCNA modules showed partial independence changes. Thy1-haSyn-associated were enriched risk PD-relevant including inflammation, autophagy, oxidative stress. Changes modest at months. Conclusions: Overexpression haSyn acutely disrupts colon. While colon are highly known mechanisms, they distinct changes, some cases, opposite direction. These findings line emerging view as multi-system disease.