Urolithin A Reverses Intranigral Rotenone-Generated Parkinsonism by Modulating DNA Methyltransferase 1 and...

Epigenetic aberrations play a key role in the neuropathogenesis of Parkinson's disease (PD). Herein, we explored the post-translational changes of DNA methyltransferase 1 (DNMT1), an epigenetic marker, in a rotenone model of PD. Rats infused with intranigral rotenone showed impaired locomotor activity and motor coordination in open-field, rotarod, and gait assays. We also noted a depression-like phenotype in the forced swim test (FST). These rotenone-generated motor and nonmotor abnormalities were reversed following peroral administration of urolithin A (UA) at 50 and 100 mg/kg doses. At the molecular level, decreased mRNA/protein expression of the NAD⁺-dependent sirtuin 1 (SIRT1) enzyme was seen in the substantia nigra (SN) of the rotenone-infused group. At the epigenetic level, we observed a decreased expression of DNMT1 and upregulated levels of acetylated DNMT1 (ac-DNMT1) in the SN of rotenone-recipient rats. UA treatment elevated the SIRT1 expression and DNMT1 deacetylation in the SN of rotenone-lesioned rats. However, DNMT1 mRNA expression remained unchanged across the groups. The in-silico binding of the catalytic region of SIRT1 to DNMT1 (over the BAH2 and catalytic domains) and its stability over a 300 ns simulation indicated the importance of SIRT1 in deacetylating DNMT1 protein. This led to UA-mediated elevation of 5-methylcytosine (5-mC) levels, promoting global DNA hypermethylation in the SN and alpha-synuclein (SNCA) promoter region methylation in the striatum. UA treatment also downregulated the SNCA gene expression and α-synuclein levels in rotenone-lesioned rats. These findings indicate that UA treatment may reverse rotenone-induced PD progression through modulation of the SIRT1/ac-DNMT1/5-mC axis within the neuroanatomical framework of the SN.