Conserved reduction of m 6 A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts
2023 | journal article. A publication with affiliation to the University of Göttingen.
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Conserved reduction of m 6 A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts
Castro-Hernández, R.; Berulava, T.; Metelova, M.; Epple, R.; Peña Centeno, T.; Richter, J. & Kaurani, L. et al. (2023)
Proceedings of the National Academy of Sciences, 120(9) art. e2204933120. DOI: https://doi.org/10.1073/pnas.2204933120
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- Authors
- Castro-Hernández, Ricardo; Berulava, Tea; Metelova, Maria; Epple, Robert; Peña Centeno, Tonatiuh; Richter, Julia; Kaurani, Lalit; Pradhan, Ranjit; Sakib, M. Sadman; Burkhardt, Susanne; Fischer, Andre
- Abstract
- N 6 -methyladenosine (m 6 A) regulates mRNA metabolism. While it has been implicated in the development of the mammalian brain and in cognition, the role of m 6 A in synaptic plasticity, especially during cognitive decline, is not fully understood. In this study, we employed methylated RNA immunoprecipitation sequencing to obtain the m 6 A epitranscriptome of the hippocampal subregions CA1, CA3, and the dentate gyrus and the anterior cingulate cortex (ACC) in young and aged mice. We observed a decrease in m 6 A levels in aged animals. Comparative analysis of cingulate cortex (CC) brain tissue from cognitively intact human subjects and Alzheimer’s disease (AD) patients showed decreased m 6 A RNA methylation in AD patients. m 6 A changes common to brains of aged mice and AD patients were found in transcripts linked to synaptic function including calcium/calmodulin-dependent protein kinase 2 ( CAMKII ) and AMPA-selective glutamate receptor 1 ( Glua1 ). We used proximity ligation assays to show that reduced m 6 A levels result in decreased synaptic protein synthesis as exemplified by CAMKII and GLUA1. Moreover, reduced m 6 A levels impaired synaptic function. Our results suggest that m 6 A RNA methylation controls synaptic protein synthesis and may play a role in cognitive decline associated with aging and AD.
- Issue Date
- 2023
- Journal
- Proceedings of the National Academy of Sciences
- Project
- SFB 1286: Quantitative Synaptologie
SFB 1286 | B06: Die Rolle von RNA in Synapsenphysiologie und Neurodegeneration
EXC 2067: Multiscale Bioimaging - Working Group
- RG A. Fischer (Epigenetics and Systems Medicine in Neurodegenerative Diseases)
RG M. Bohnsack (Molecular Biology) - ISSN
- 0027-8424
- eISSN
- 1091-6490
- Language
- English
- Sponsor
- Deutsche Forschungsgemeinschaft 501100001659