A COMMON INFLAMMATION-MIRNA AXIS DRIVES THE MOLECULAR CONVERGENCE OF PARKINSON'S DISEASE, DEPRESSIVE DISORDER, AND GUT DYSFUNCTION

Parkinson's disease (PD) frequently co-occurs with depressive disorder (DD) and gastrointestinal dysfunction, suggesting a common inflammatory etiology along the gut-brain axis. We hypothesized that a specific miRNA-mediated inflammatory profile underlies this clinical triad, representing a point of pathological convergence. We profiled a panel of inflammatory bowel disease (IBD)-associated miRNAs and inflammatory mediators, and glial response in postmortem brain tissue (dlPFC/Caudate) from PD, DD, and control subjects. To investigate causality and gut-brain axis involvement, we used a PD mouse model with α-synucleinopathy in dorsal raphe serotonin neurons and a corticosterone (CORT)-induced depression-like model. Animals were assessed for depressive-like behaviors and GI dysmotility, with parallel molecular profiling performed in brain (mPFC/CPu) and ileum. We identified a conserved miRNA pattern in the brains of both PD and DD patients, characterized by the downregulation of miR-199a-5p and miR-219a-5p and upregulation of miR-200a-3p. This dysregulation correlated with an NFκB1-driven pro-inflammatory state (evidenced by increased expression of TNFα, IFN-γ) and changes in glial response. In mice, both PD and CORT models exhibited a depression-like phenotype and gastrointestinal deficits. Notably, the specific human brain miRNA and cytokine pattern was replicated in both the murine brain and ileum, providing direct evidence of a parallel pathological process spanning the gut-brain axis. Our study defines a specific miRNA-inflammatory axis as a central molecular convergence mechanism connecting the pathophysiology of PD, DD, and gut dysfunction. Targeting this triad represents a novel therapeutic strategy to simultaneously address the motor, psychiatric, and gastrointestinal burdens of these comorbidities.