Perillaldehyde alleviates Parkinson's disease via the gut microbiota-5-methyltetrahydrofolate-homocysteine methylation axis.

Abstract

<p>BACKGROUND: Gut microbiota dysbiosis is critically involved in the pathogenesis of Parkinson's disease (PD), yet therapeutic strategies targeting the gut-brain axis remain underexplored. Perillaldehyde (PAH), a natural monoterpene aldehyde primarily extracted from Perilla frutescens, exhibits significant neuroprotective and anti-inflammatory properties in vitro, but its effects on PD in vivo, particularly regarding microbiota-mediated mechanisms, have yet to be fully elucidated. PURPOSE: This study aims to investigate the anti-PD effects of PAH with a specific focus on the role of intestinal flora in it. METHODS: The protective effects of PAH on motor function and dopaminergic neurons were evaluated in a rotenone (ROT)-induced PD mice model using behavioral tests, immunofluorescence, and Western blotting. The involvement of gut microbiota was assessed through 16S rRNA sequencing, antibiotic-induced flora depletion, and fecal microbiota transplantation (FMT). Key metabolites were identified via metabolomics and validated by replenishment assays. The underlying molecular mechanism was further clarified through mitochondrial function analysis and gene knockdown experiments. RESULTS: PAH relieves PD-like pathologies in ROT- induced mice, such as motor disorders, gastrointestinal dysfunction, and nerve damage. FMT and co-housing experiments confirmed that the gut microbiota is essential for PAH's neuroprotective effects. Metabolomic analysis further showed that PAH can increase the levels of 5-methyltetrahydrofolate (5-MTHF) in mice serum. Supplementing 5-MTHF restores the weakened neuroprotective effect of PAH caused by microbiota clearance. Further in vitro mechanistic studies indicated that 5-MTHF improves neuronal mitochondrial dysfunction and alleviates ROT-induced nerve damage by lowering neurotoxic homocysteine (Hcy) levels, while knocking down the methionine synthase (Mtr) eliminates the mitochondrial protection provided by 5-MTHF. CONCLUSION: These findings uncover a gut-brain axis mechanism by which PAH exerts anti-PD effects through enhancing 5-MTHF production, thereby promoting Mtr-mediated Hcy clearance and restoring mitochondrial redox homeostasis.</p>