Differential A-to-I editing of SINE B2 RNAs unveils an epitranscriptome response to Aβ neurotoxicity.

Overview

1. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada
2. Paul Albrechtsen Research Institute CCMB, Winnipeg, Canada
3. Department of Neuroscience, Canadian Centre for Behavioral Neuroscience, University of Lethbridge, Lethbridge, Canada
4. Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada
5. Department of Psychiatry, McGill University, Montreal, Canada
6. Douglas Hospital Research Center, Montreal, Canada

Abstract

Adenosine-to-inosine (A-to-I) RNA editing is a major epitranscriptomic mechanism, yet its contribution to non-coding RNA regulation during neurodegeneration is largely unknown. SINE B2 RNAs represent the dominant editing substrates in mice and have been shown to regulate gene expression. Here, we introduce and validate a repeat-aware bioinformatics framework that enables position-specific quantification of A-to-I editing within SINE RNAs, which has been challenging using standard genome-based pipelines. Applying this approach, we identify discrete editing hotspots in mouse SINE B2 RNAs that are selectively increased during early amyloid beta pathology in independent mouse models and in hippocampal neurons exposed to amyloid beta toxicity. Functional perturbation of ADAR activity alters both B2 RNA editing levels and the expression of B2 RNA–regulated genes, directly linking RNA editing to SINE-mediated transcriptional control. Nanopore sequencing confirmed increased RNA modification signals at these regions. Together, our findings establish a previously unrecognized epitranscriptomic response to amyloid beta neurotoxicity mediated by site-specific A-to-I editing of SINE RNAs.

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

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Data

Datasets cited

• geo:GSE316378 — at NCBI GEO; found in “Data Availability”

Data Availability

Raw Illumina RNA-seq data (fastq files) for the APP/WT mouse and HT-22 transcriptome data originate from our previous study (Cheng et al, 2020) and are deposited in GEO with access number GSE149243 (https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149243). Immunohistochemistry and behavioral studies of this mouse model are described in our previous study (Mehla et al, 2019). The tested mice carry the Arctic, Swedish, and Beyreuther/Iberian mutations (APPNL-G-F/NL-G-F) and were provided by the RIKEN Center for Brain Science, Japan; the colony was maintained at the University of Lethbridge vivarium. The external mouse dataset comprises RNA-seq data from mice with human transgenes for mutant forms of APP and PSEN1, as well as WT controls. The dataset was retrieved from the GEO access number GSE136861 (https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE136861) series.

Novel RNA-seq data of this study have been deposited to GEO with access number GSE316378 (https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE316378) for Illumina and nanopore RNA-seq of RNA from the HT-22 cells of the AntiAdar experiments and GSE171312 (https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE171312) for nanopore RNA-seq of RNA from the mice hippocampi of the APPNL-G-F/NL-G-F mice mentioned above.

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

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 13 MeSH terms, 6 funders, 69 references.

Cite

This paper

Mitchell, L., Saville, L., Gollen, B., Haight, T., Roy, R., Turner, C., Cheng, Y., Kovalchuk, I., Mohajerani, M. H., & Zovoilis, A. (2026). Differential A-to-I editing of SINE B2 RNAs unveils an epitranscriptome response to Aβ neurotoxicity. Life science alliance, 9(9), e202603668. https://doi.org/10.26508/lsa.202603668

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