Distinct patterns of gene expression changes in the colon and striatum of young mice overexpressing alpha-synuclein support Parkinson Disease as a multi-system process

Background Parkinson Disease (PD) is increasingly being recognized as a disease of the gut-brain axis. Overexpression of human wild type α–synuclein under the neuron-specific Thy1 promoter (Thy1-haSyn) is a well-characterized mouse model of PD. In addition to a progressive motor phenotype, Thy1-haSyn mice have delayed colonic transit at three months of age mirroring prodromal constipation common in human PD. Identification of initial molecular changes in the gastrointestinal tract in PD could lead to early detection of PD and/or gut-targeted therapies to prevent motor symptoms in PD. Methods Colon and striatum gene expression profiling was performed in Thy1-haSyn and wild type (WT) mice aged 1 month and 3 months using 3′ RNA sequencing. Analysis of transcriptomic data included identification of differentially expressed genes, gene set enrichment analysis and weighted gene co-expression network analysis (WGCNA). WGCNA results were further analyzed by linear regression to identify modules most strongly associated with Thy1-haSyn in the colon and striatum, as well as in a combined multivariate model. Module annotation included enrichment for gene ontology terms, cell type signatures and risk genes. Results Differential gene expression in Thy1-haSyn vs WT was greater at one vs three months in both the colon and striatum. There was an opposite pattern of enrichment of mitochondrial genes related to PD (KEGG PD pathway) in striatum (enriched in WT) and colon (enriched in Thy1-haSyn). Colon Thy1-haSyn-associated WGCNA modules were enriched for PD risk genes and PD-relevant pathways including inflammation, autophagy, and oxidative stress. When combined with striatum modules, colon modules remained independent predictors of Thy1-haSyn genotype and increased the model fit (p = 0.048). Conclusions Overexpression of alpha synuclein acutely disrupts gene expression in the colon. While changes in colon gene expression are highly related to known PD-relevant mechanisms, they are distinct from brain changes and in some cases opposite in direction. These findings are in line with the emerging view of PD as a multi-system disease.