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Here, we investigate the role of RNA modification in PD, following observations of selective m\n                    <jats:sup>6<\/jats:sup>\n                    A hypomethylation in the substantia nigra (SN) of mouse PD models and dysregulated\n                    <jats:italic>METTL3<\/jats:italic>\n                    and\n                    <jats:italic>ALKBH5<\/jats:italic>\n                    expression in dopaminergic (DA) neurons from patients with PD. We found preferential m\n                    <jats:sup>6<\/jats:sup>\n                    A 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.\n                    <jats:italic>Mettl3<\/jats:italic>\n                    <jats:sup>K480R\/+<\/jats:sup>\n                    mice exhibited progressive METTL3 reduction and m\n                    <jats:sup>6<\/jats:sup>\n                    A hypomethylation in the SN, leading to progressive DA neuron loss, phospho-\u03b1-synuclein increase, and levodopa-responsive motor and nonmotor deficits, mimicking PD progression. Dopamine transporter\u2013specific METTL3 knockout mice recapitulate m\n                    <jats:sup>6<\/jats:sup>\n                    A hypomethylation, neurodegeneration, and levodopa-responsive parkinsonism. Mechanistically, m\n                    <jats:sup>6<\/jats:sup>\n                    A deficiency disrupted mitochondrial biogenesis and function through regulating\n                    <jats:italic>Tfam<\/jats:italic>\n                    expression, while mitochondrial dysfunction reciprocally impaired m\n                    <jats:sup>6<\/jats:sup>\n                    A deposition, creating a pathogenic loop. Importantly, supplementation with S-adenosylmethionine (SAMe) enhanced m\n                    <jats:sup>6<\/jats:sup>\n                    A modification, disrupted the pathogenic loop, and alleviated parkinsonism in mouse models. Our findings revealed m\n                    <jats:sup>6<\/jats:sup>\n                    A 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.\n                  <\/jats:p>","DOI":"10.1172\/jci197183","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T16:01:56Z","timestamp":1773763316000},"source":"Crossref","is-referenced-by-count":3,"title":["m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with mitochondria"],"prefix":"10.1172","volume":"136","author":[{"given":"Sun","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihuan","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiling","family":"Mo","sequence":"additional","affiliation":[{"name":"Guangzhou KingMed Diagnostics Group Co. 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