FTO Dependent Trim14 m6A Modification Regulates Neuroinflammation in MPTP-Induced Parkinson's Disease Models via the RhoA/ROCK Pathway

Microglia-mediated inflammation is a major contributor to the development of Parkinson's disease (PD) and N6-Methyladenosine (m6A) has been implicated PD. Here, we explored whether m6A modification is associated with microglia-mediated inflammation using MPTP-treated mice and MPP⁺-exposed BV2 cells. AAV-mediated gene manipulation, immunostaining, and methylated RNA immunoprecipitation-quantitative PCR were used to explore the underlying mechanisms. We found microglial m6A modification decreased and microglial fat mass and obesity-associated protein (FTO) expression increased in BV2 cells treated with MPP⁺. Knockdown of FTO expression increased Trim14 expression and protected dopaminergic neurons; Trim14 overexpression significantly blocked the activation of RhoA-ROCK pathway. In MPTP-induced mice, FTO upregulation removes m⁶A modification from Trim14 mRNA, leading to Trim14 downregulation and subsequent activation of the RhoA-ROCK pathway, thereby exacerbating neuroinflammation. The FTO-Trim14 axis represents a potential therapeutic target for PD.