Abstract

Dopaminergic (DA) neurons are highly susceptible to endoplasmic reticulum (ER) burden and redox imbalance, which drive their degeneration and contribute to Parkinson’s disease (PD) pathogenesis. Previous work established METTL14-mediated N6-methyladenosine (m6A) modification as critical for dopaminergic (DA) neuron survival. Here, we delineate the underlying mechanism by which m6A dysregulation triggers neurodegeneration through the post-transcriptional modulation of key target genes. Using Mettl14 conditional knockout mice, we identified the ER calcium channel ATP2A3—a key calcium homeostasis regulator and known PD biomarker—as a major target of METTL14. METTL14 deficiency significantly reduced ATP2A3 expression, thereby exacerbating ER homeostasis and oxidative stress, ultimately leading to DA neuronal death. Restoring METTL14 in vivo alleviates motor deficits and neurodegeneration. Our findings reveal that m6A-mediated regulation of ATP2A3 bridges RNA epigenetic dysregulation to PD pathogenesis, highlighting this axis as a potential therapeutic target in this disease.