Alzheimer’s disease pathogenetic progression is associated with changes in regulated retained introns and editing of circular RNAs

Maquera, Karol Andrea Arizaca; Welden, Justin R.; Margvelani, Giorgi; Sardón, Sandra C. Miranda; Hart, Samantha N.; Robil, Noémie; Hernandez, Alvaro G.; Grange, Pierre de la; Nelson, Peter T.; Stamm, Stefan

doi:10.3389/fnmol.2023.1141079

Cited by 7 publications

(3 citation statements)

References 60 publications

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“…We previously reported that circular RNAs are translated after undergoing adenosine to inosine RNA editing, caused by ADAR1 or ADAR2 [12,29]. There are two major isoforms of ADAR1: ADAR1-p150 and ADAR1-p110.…”

Section: Resultsmentioning

confidence: 99%

Influence of FTDP-17 mutants on circular Tau RNAs

Margvelani,

Welden,

Maquera

et al. 2023

Preprint

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At least 53 mutations in the microtubule associated protein tau gene (MAPT) have been identified that cause frontotemporal dementia. 47 of these mutations are localized between exons 7 and 13. They could thus affect the formation of circular RNAs (circRNAs) from the MAPT gene that occur through backsplicing from exon 12 to either exon 10 or exon 7. We analyzed representative mutants and found that five FTDP-17 mutations increase the formation of 12->7 circRNA and three different mutations increase the amount of 12->10 circRNA. CircRNAs are translated after undergoing adenosine to inosine RNA editing, catalyzed by ADAR enzymes. We found that the interferon induced ADAR1-p150 isoform has the strongest effect on circTau RNA translation. ADAR1-p150 activity had a stronger effect on circTau RNA expression and strongly decreased 12->7 circRNA, but unexpectedly increased 12->10 circRNA. In both cases, ADAR-activity strongly promoted translation of circTau RNAs. Unexpectedly, we found that the 12->7 circTau protein interacts with eukaryotic initiation factor 4B (eIF4B), which is reduced by four FTDP-17 mutations located in the second microtubule domain. These are the first studies of the effect of human mutations on circular RNA formation and translation. They show that point mutations influence circRNA expression levels, likely through changes in the secondary pre-mRNA structures. The effect of the mutations is surpassed by editing of the circular RNAs, leading to their translation. Thus, circular RNAs and their editing status should be considered when analyzing FTDP-17 mutations.

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Section: Resultsmentioning

confidence: 99%

Influence of FTDP-17 mutants on circular Tau RNAs

Margvelani,

Welden,

Maquera

et al. 2023

Preprint

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“…Notably, this pattern of dysregulation is not mirrored in the linear counterparts of these circRNAs, which exhibit no significantly differential expression between AD and control samples (Fig) (Rybak-Wolf A et al 2015 ). A study using poly(A) + RNA samples obtained from AD brains also displayed no correlation in expression levels between the most abundant circRNAs and their mRNA counterparts through ranking (Arizaca Maquera KA et al 2023 ). The heightened expression of dysregulated circRNAs could potentially serve as indicative markers of their involvement in AD pathology.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Circular Transcriptome in Alzheimer’s Disease Brain

Gao,

Xu,

Cheng

et al. 2024

J Mol Neurosci

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Circular RNAs (circRNAs) are a subclass of non-coding RNAs which have demonstrated potential as biomarkers for Alzheimer’s disease (AD). In this study, we conducted a comprehensive exploration of the circRNA transcriptome within AD brain tissues. Specifically, we assessed circRNA expression patterns in the dorsolateral prefrontal cortex collected from nine AD-afflicted individuals and eight healthy controls. Utilising two circRNA detection tools, CIRI2 and CIRCexplorer2, we detected thousands of circRNAs and performed a differential expression analysis. CircRNAs which exhibited statistically significantly differential expression were identified as AD-specific differentially expressed circRNAs. Notably, our investigation revealed 120 circRNAs with significant upregulation and 1325 circRNAs displaying significant downregulation in AD brains when compared to healthy brain tissue. Additionally, we explored the expression profiles of the linear RNA counterparts corresponding to differentially expressed circRNAs in AD-afflicted brains and discovered that the linear RNA counterparts exhibited no significant changes in the levels of expression. We used CRAFT tool to predict that circUBE4B had potential to target miRNA named as hsa-miR-325-5p, ultimately regulated CD44 gene. This study provides a comprehensive overview of differentially expressed circRNAs in the context of AD brains, underscoring their potential as molecular biomarkers for AD. These findings significantly enhance our comprehension of AD’s underlying pathophysiological mechanisms, offering promising avenues for future diagnostic and therapeutic developments.

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“…Despite the challenges posed by the short reads and 3′ bias in the 10x Genomics’ scRNA-seq data ( Westoby et al, 2020 ), a good understanding of splicing changes can still be achieved due to the presence of a large number of junctional reads in the datasets and the application of a robust statistical approach ( Figure 1B ). Furthermore, due to the strong correlation between splicing changes and Braak NFT stages in AD ( Arizaca Maquera et al, 2023 ), the utilization of NFT and NGE single-cell data can provide a broader view of ASEs in PFC neuronal subtypes based on NFT pathogenesis and ASEs in different brain cell types based on Braak stages, respectively. A broad identification of ASEs can be gained by analyzing splicing alterations in various cell populations at different stages of AD progression.…”

Section: Introductionmentioning

confidence: 99%

Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective

Farhadieh,

Ghaedi

2023

Front. Mol. Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative disease with no effective cure that attacks the brain’s cells resulting in memory loss and changes in behavior and language skills. Alternative splicing is a highly regulated process influenced by specific cell types and has been implicated in age-related disorders such as neurodegenerative diseases. A comprehensive detection of alternative splicing events (ASEs) at the cellular level in postmortem brain tissue can provide valuable insights into AD pathology. Here, we provided cell-level ASEs in postmortem brain tissue by employing bioinformatics pipelines on a bulk RNA sequencing study sorted by cell types and two single-cell RNA sequencing studies from the prefrontal cortex. This comprehensive analysis revealed previously overlooked splicing and expression changes in AD patient brains. Among the observed alterations were changed in the splicing and expression of transcripts associated with chaperones, including CLU in astrocytes and excitatory neurons, PTGDS in astrocytes and endothelial cells, and HSP90AA1 in microglia and tauopathy-afflicted neurons, which were associated with differential expression of the splicing factor DDX5. In addition, novel, unknown transcripts were altered, and structural changes were observed in lncRNAs such as MEG3 in neurons. This work provides a novel strategy to identify the notable ASEs at the cell level in neurodegeneration, which revealed cell type-specific splicing changes in AD. This finding may contribute to interpreting associations between splicing and neurodegenerative disease outcomes.

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Alzheimer’s disease pathogenetic progression is associated with changes in regulated retained introns and editing of circular RNAs

Cited by 7 publications

References 60 publications

Influence of FTDP-17 mutants on circular Tau RNAs

Influence of FTDP-17 mutants on circular Tau RNAs

Investigation of the Circular Transcriptome in Alzheimer’s Disease Brain

Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective

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