Knockdown of fat mass and obesity alleviates the ferroptosis in Parkinson's disease through m6A‐NRF2‐dependent manner
Pengfei Pang, Shirong Zhang, Shirong Zhang, Xinxin Fan, Shitao Zhang, Shitao Zhang
Abstract
Abstract Emerging evidence has suggested that N 6 ‐methyladenosine (m 6 A) regulates the pathology of Parkinson's disease (PD). Nevertheless, the function of demethylase fat mass and obesity (FTO) associated pathogenesis is still not fully elucidated. Here, this research findings revealed that m 6 A‐modification was decreased in PD models, meanwhile, the FTO level upregulated in the PD models. Functionally, in N‐methyl‐4‐phenylpyridinium (MPP+) treated SH‐SY5Y cells, the ferroptosis significantly upregulated and FTO silencing mitigated the ferroptosis phenotype. Moreover, in silico assays indicated that nuclear factor erythroid 2‐related factor‐2 (NRF2) acted as the target of FTO, and FTO demethylated the m 6 A modification from NRF2 mRNA. Furthermore, FTO impaired the NRF2 mRNA stability via m 6 A‐dependent pathway. Thus, our findings illustrated an important role of FTO on PD through m 6 A‐NRF2‐ferroptosis manner. Taken together, the study revealed the potential function of FTO on PD nervous system diseases.