m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with mitochondria

Despite substantial progress in understanding the molecular pathology of Parkinson's disease (PD), the underlying drivers of PD in many cases remain unknown. Here, we investigate the role of RNA modification in PD, following observations of selective m6A hypomethylation in the substantia nigra (SN) of mouse PD models and dysregulated METTL3 and ALKBH5 expression in dopaminergic (DA) neurons from patients with PD. We found preferential m6A deposition on transcripts of PD risk genes and what we believe to be a previously unreported heterozygous METTL3 p.K480R mutation in patients with PD. Mettl3K480R/+ mice exhibited progressive METTL3 reduction and m6A hypomethylation in the SN, leading to progressive DA neuron loss, phospho-α-synuclein increase, and levodopa-responsive motor and nonmotor deficits, mimicking PD progression. Dopamine transporter-specific METTL3 knockout mice recapitulate m6A hypomethylation, neurodegeneration, and levodopa-responsive parkinsonism. Mechanistically, m6A deficiency disrupted mitochondrial biogenesis and function through regulating Tfam expression, while mitochondrial dysfunction reciprocally impaired m6A deposition, creating a pathogenic loop. Importantly, supplementation with S-adenosylmethionine (SAMe) enhanced m6A modification, disrupted the pathogenic loop, and alleviated parkinsonism in mouse models. Our findings revealed m6A dysregulation as an important contributor to PD pathogenesis, provide a valuable preclinical mouse model for PD progression, and highlight RNA methylation-targeted therapies as a promising strategy for PD intervention.