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.
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Data availability
The datasets generated and analyzed during the current study are not publicly available due to privacy, but are available from the corresponding author upon reasonable request.
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Acknowledgements
The authors would like to thank Dr. Li Hua-bing (Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, School of Medicine, Shanghai Jiao Tong University) for his support to provide us the Mettl14-loxp mice. L.Y. and W.D.L. discloses support for the research of this work from the National Natural Science Foundation of China (81601125, 32220103006), the Department of Science and Technology of Sichuan Province (2022YFS0597) and the Clinical Medicine Discipline Development Fund from UESTC (YXYLCJJ202402015). Y.Z.L. discloses support for the research of this work from the Department of Science and Technology of Sichuan Province (2025ZNSFSC1743).
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L.Y., W.D.L. and H.S.J. conceptualized the project. L.Y., H.S.J., Z.Y.W. and J.Y. contributed to experimental design and data interpretation. Y.T., Z.H.L., Q.T and F.W. performed experiments and analyzed data helped by X.M.C., J.L.X., Q.T. Y.Z.L., Y.Q.H., K.F.W. and M.J.L., L.Y. and Y.T. wrote the paper with input from all the authors. L.Y., W.D.L. and H.S.J. and supervised the project, provided resources and acquired funds.
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Teng, Y., Liu, Z., Wei, F. et al. Loss of METTL14 in dopaminergic neurons disrupts ER homeostasis via m6A-dependent regulation of Atp2a3 mRNA: Implications for Parkinson’s Disease. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01318-7
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DOI: https://doi.org/10.1038/s41531-026-01318-7
