METTL14 is decreased and regulates m⁶A modification of α‐synuclein in Parkinson's disease

Abstract

N6-methyladenosine (m6A), an emerging modification of messenger RNA, has been implicated in many biological processes. However, its role in Parkinson's disease (PD) remains largely unknown. Here, we investigated the role of m6A modification and its underlying mechanism in PD. First, 86 individuals with PD and 86 healthy controls were recruited from a pilot multicenter cohort. Levels of m6A and its modulators in peripheral blood mononuclear cells of patients with PD and controls were measured using an m6A RNA methylation quantification kit and quantitative real-time PCR. The underlying mechanism of m6A modification in PD was investigated in vitro through RNA immunoprecipitation assay, RNA stability assay, gene silencing or overexpression, western blot, and confocal immunoassay. The results show that mRNA levels of m6A, METTL3, METTL14, and YTHDF2 in patients with PD were significantly lower than in healthy controls, and METTL14 was the main factor involved in abnormal m6A modification. Area under the curve (AUC) analysis suggests METTL14 may provide excellent diagnostic capability for PD, especially when combined with plasma α-synuclein (α-syn). Spearman correlation analysis identified that METTL14 was moderately negatively correlated with plasma α-syn and the motor function of PD.Mechanistic experiments demonstrated that Mettl14 targets and regulates the expression of the α-syn gene using its methylation function. Overexpression of Mettl14 dramatically increased m 6 A modification of α-syn mRNA and weakened its stability.Further results suggest that α-syn mRNA was modified by Mettl14 binding of an m 6 A motif in the coding region of α-syn mRNA, while the reading protein Ythdf2 was involved in recognizing m 6 A-modified α-syn mRNA. Taken together, our results reveal the potential of METTL14 as a novel diagnostic biomarker for PD and identify modification of pathogenic α-syn protein by METTL14 via an m 6 A-YTHDF2-dependent mechanism.

Emerging Roles and Mechanisms of RNA Modifications in Neurodegenerative Diseases and Glioma

“…This escalation contributes to oxidative stress, an increase in calcium influx, and ultimately, it accelerates the degeneration or cell death of these dopaminergic neurons [ 92 ]. In another study, METTL3, METTL14, and YTHDF2 were significantly downregulated in PD patient blood mononuclear cells with METTL14 being the main factor involved in the abnormal m6A modification of α-synuclein mRNA [ 93 ]. Mettl14 targets and regulates the expression of the α-synuclein gene by binding an m6A motif in the coding region which eventually modifies α-synuclein mRNA and weakens its stability.…”

“…Mettl14 targets and regulates the expression of the α-synuclein gene by binding an m6A motif in the coding region which eventually modifies α-synuclein mRNA and weakens its stability. Spearman correlation analysis showed METTL14 levels inversely correlated with plasma α-synuclein concentrations and motor function of PD patients [ 93 ]. Furthermore, the advancement in RNA sequencing capabilities has facilitated the detailed exploration of RNA editing occurrences across the whole transcriptome, offering deeper insights into A-to-I editing in various diseases.…”

Emerging Roles for DNA 6mA and RNA m6A Methylation in Mammalian Genome

“…The excessive loss of dopaminergic neurons occurs before the onset of motor symptoms in PD patients [ 217 ]. m6A modification variants were found in PD patients [ 218 ], and METTL3, METTL14, and YTHDF2 mRNA levels were lower in PD patients, suggesting that PD pathogenesis may be regulated via m6A modification [ 154 ].…”

“…The conditional knockout of METTL14 significantly reduced the overall mRNA m6A levels and downregulated Nurr1, pitx3, and EN1 expressions in the substantia nigra region, which was associated with behavioral motor impairment [ 158 ]. Furthermore, METTL14 regulates the stability of α-syn mRNA [ 154 ]. The HNRNPC expression level is low in PC12 cells, while HNRNPC overexpression inhibits apoptosis and immune inflammation [ 159 ].…”

Potential role of N6-methyladenosine modification in the development of Parkinson’s disease

“…The expression of m6a-related proteins, including METTL3, METTL14, and YTHDF2, was also notably downregulated. Further research indicated that METTL14 influences the stability of α-Syn mRNA and modulates α-Syn expression in an m6A-dependent manner, potentially offering valuable diagnostic information for PD ( He et al, 2023 ).…”