Novel Insights Into the Association Between Parkinson's Disease and Constipation: Role of <scp>SHMT2</scp> as a Promising Biomarker

AIMS: We aimed to investigate the shared molecular pathways between Parkinson's disease (PD) and constipation using bioinformatics analysis. METHODS: Differentially expressed genes (DEGs) were identified via the R limma package, and Weighted Gene Co-Expression Network Analysis (WGCNA) was conducted to identify hub modules. Biological enrichment analysis clarified the biological processes involved. A gene-gene interaction (GGI) network was constructed to identify shared hub biomarkers. Validation of these biomarkers was done in vitro with α-synuclein (α-syn)-treated SH-SY5Y cells and in vivo through α-syn-induced PD mouse models, A53T transgenic mice, and loperamide-induced constipation models. RESULTS: Numerous DEGs were identified in both conditions, with 14 shared DEGs found through the intersection of core modules and upregulated DEGs. These DEGs are primarily involved in energy metabolism, protein modification, and mitochondrial function. Five key hub genes were identified using the GGI network and gene topological analysis. Notably, Serine hydroxymethyltransferase 2 (SHMT2) expression was significantly upregulated after α-syn treatment in vitro. Immunohistochemical and immunofluorescence analyses revealed elevated SHMT2 expression in brain and colon tissues in PD mouse models (p < 0.001), whereas in constipation models, SHMT2 was only elevated in the colon wall with no significant expression in the enteric nervous system. CONCLUSION: Our findings offer new views on the molecular link between PD and constipation, suggesting SHMT2 as a possible biomarker and therapeutic target for PD symptoms.