ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2025
Sequence Diversity and Encoded Enzymatic Differences of Monocistronic L1 ORF2 mRNA Variants in the Aged Normal and Alzheimer's Disease Brain.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Disrupted PQBP1-HNRNPU-LINE-1 axis underlies aberrant neurodevelopment in renpenning syndrome.Molecular psychiatry · 2026Article
- Locus-specific LINE-1 mRNA expression reflects cell-type- and stimulus-specific senescence states.Nucleic acids research · 2026Article
- RNA isoform diversity, splicing variants and switching in single cells of the Alzheimer's disease brain.Communications biology · 2026Article
- Unveiling Aging and Alzheimer's Disease-Associated Dynamics of LINE1 DNA Content and Protein Expression in Mouse Brains.Aging cell · 2025Article
- RNA isoform diversity, splicing variants, and switching in single cells of the Alzheimer's disease brain.Research square · 2025Article
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7 authors.
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Abstract
Reverse transcriptase (RT) activity in the human brain has been inferred through somatic retroinsertion/retrotransposition events; however, actual endogenous enzymatic activities and sources remain unclear. L1 (LINE-1) retrotransposons bicistronically express ORF2, containing RT and endonuclease (EN) domains, and RNA-binding protein ORF1, together enabling L1 retrotransposition and contributing to somatic genomic mosaicism. Here, we assessed endogenous RT activities and L1 mRNA diversity from cerebral cortex samples of 31 Alzheimer's disease (AD) and nondiseased (ND) brains (both sexes) using enzymatic functional assays, targeted PacBio HiFi long-read sequencing, and quantitative spatial transcriptomics. Expected bicistronic, full-length L1 transcripts were absent from most samples, constituting <0.01% of L1 sequences, of which >80% were noncoding. Monocistronic ORF1 and ORF2 transcripts were identified across all samples, consistent with quantitative spatial transcriptomics that identified discordant ORF2 and ORF1 expression in neurons. All brains had RT activity, with AD samples showing less activity, consistent with neuronal loss of terminal AD versus aged ND donors. Brain RT activity was higher in the gray matter and correlated with increased neuronal ORF2 expression, further supporting neuronal contributions. Remarkably, >550 protein-encoding, poly(A
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