Objective: The aim of this study is to explore the function and mechanism of RNA m⁶A modification in gut-derived inflammation of Parkinson’s disease (PD).

Background: Abnormal regulation of RNA modification is related to the progression of neurodegenerative diseases. Gut-derived inflammation plays a vital function in the progression of PD. However, the role of RNA m⁶A modification in intestinal inflammation of PD remains unknown.

Method: We used PCR, Western blot and immunofluorescence to detect METTL14 in colonic tissue of PD A53T α-synuclein transgenic (Tg) mice and in vitro PD model of the intestinal epithelial barrier. The mechanism underlying METTL14 was investigated in vitro experiments by MeRIP-Seq, RIP and luciferase reporter assays.

Results: We found that METTL14 was decreased in colonic tissue of PD mice. Overexpression of METTL14 in PD Tg mice significantly reduced intestinal inflammation, neurodegeneration and alleviated intestinal dysfunction and dyskinesia, when compared with Tg mice or wild-type mice. By using Caco-2 cells co-treated with LPS and α-synuclein as in vitro PD model of the intestinal epithelial barrier, we found H3K79me3 demethylation in the promoter of METTL14 induced by KDM2B (a lysine-specific histone demethylase) could lead to decrease METTL14 transcription. Additionally, we identified that TLR4 could be m⁶A-modified by METTL14. Overexpression of METTL14 increasingly promoted TLR4 mRNA m⁶A modification and downregulated TLR4 mRNA expression level, subsequently resulted in less intestinal inflammation and alleviating intestinal dysfunction.

Conclusion: Our study suggests that METTL14 mediated-mRNA m⁶A modification is involved in the pathogenesis of PD through regulating gut-brain axis and provides molecular mechanisms for clinical treatment of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-n6-methyladenosine-mrna-methylase-mettl14-regulates-tlr4-mediated-intestinal-dysfunction-in-parkinsons-disease/