Abstract
Background
Parkinson's disease (PD) is a neurodegenerative disease caused by environmental and genetic factors. Manganese (Mn) exposure is a major environmental cause of PD. Cellular and molecular mechanism of Parkinsonism caused by Mn has not been explored clearly. In addition, patients with Mn-induced Parkinsonism show poor therapeutic response to levodopa. Therefore, there is need to explore the mechanisms underlying neurotoxicity of Mn exposure.
Methods
In short, we used SH-SY5Y cells and C57BL/6 mice to characterize Mn-induced Parkinsonism. We measured the behavioral, histological, ultrastructural and nigro-striatal projection system changes, cell viability, axon growth, and other target indicator levels, which led to the discovery of a novel mechanism of Mn-induced neurotoxicity.
Results
The findings of the current study showed that inhibition of fat mass and obesity-associated protein (FTO)-mediated demethylation of N6-methyladenosine (m6A) mRNA aggravates Mn-induced motor dysfunction. Notably, FTO level is low in Mn exposure model mice and enhances occurrence of dyskinesia in mice. Over-expression of FTO reduces m6A methylation in the key axon guiding molecules of nigro-striatal projection system, including ephrin-A5 and ephrin-B2. It increases ephrin-B2 mRNA decay through the m6A reader YT521-B homology domain family proteins 2 (YTHDF2).
Conclusions
The findings of this study show that FTO, a m6A demethylase, performs an indispensable function in Mn-induced Parkinsonism. Notably, re-expression of FTO and ephrin-B2 improved motor dysfunction after Mn exposure.
Protective role of mRNA demethylase FTO on axon guiding molecules of nigro-striatal projection system in manganese-induced Parkinsonism
