The epitranscriptomic m6A RNA modification modulates the synapse in ageing and in a mouse model of synucleinopathy.

Overview

1. Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen,Göttingen, Germany
2. Department of Neurology, University Medical Centre Göttingen,Göttingen, Germany
3. Department for Systems Medicine and Epigenetics, German Center for Neurodegenerative Diseases (DZNE),Göttingen, Germany
4. Paracelsus Elena Klinik,Kassel, Germany
5. Department of Psychiatry and Psychotherapy, University Medical Center Göttingen,Göttingen, Germany
6. Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen,Göttingen, Germany
7. Faculdade de Medicina e Ciências Biomédicas, Algarve Biomedical Center Research Institute, Universidade do Algarve,Faro, Portugal
8. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University,Newcastle Upon Tyne, UK
9. Scientific employee with an honorary contract at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany

Abstract

N6-methyladenosine (m6A) is the most abundant transcriptional modification in eukaryotic RNA, regulating RNA fate. While the functions of m6A in the development of the mammalian brain have been extensively studied, its role in synaptic plasticity, and brain function remain underexplored. The involvement of this modification in Parkinson’s disease and other synucleinopathies has only recently been studied, and needs further investigation. Here, we investigated the m6A epitranscriptome using MeRIP-seq in A30P-aSyn transgenic mice (aSyn Tg). We observed hypermethylation of synaptic genes in young aSyn Tg mice compared to age-matched control mice. The methylation was reduced during ageing. Using immunofluorescence imaging and biochemical analysis, we further investigated the levels and distribution of m6A regulatory enzymes—writer, METTL3, reader, YTHDF1, and eraser, FTO, in the cortex, striatum, hippocampus, and cerebellum of aSyn Tg and control mice, and in primary cortical neuronal cultures. While the levels of these proteins were similar, METTL3 was found in the nucleus and in the post-synaptic compartment in neurons, suggesting it may play a role in methylation at the post-synapse. Our findings suggest that alterations in the regulation of m6A RNA methylation may be associated with neurodegeneration and ageing and it may play a significant role at the synapse.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE275432, at NCBI GEO; found in “Data availability”

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request. All raw data files for MeRIP-seq are available on the GEO database (GSE275432). To review GEO accession GSE275432 on https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE275432, enter token otebmkqmxdkrlot into the box.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 2 keywords, 1 funder, 90 references, 3 RRIDs.

Cite

This paper

Chopra, A., Xylaki, M., Yin, F., Castro-Hernández, R., Merghani, M., Grande, V., Mollenhauer, B., Fischer, A., & Outeiro, T. F. (2026). The epitranscriptomic m6A RNA modification modulates the synapse in ageing and in a mouse model of synucleinopathy. NPJ Parkinson's disease, 12(1), 117. https://doi.org/10.1038/s41531-026-01362-3

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