Alu RNA and their roles in human disease states

Gussakovsky, Daniel; McKenna, Sean Andrew

doi:10.1080/15476286.2021.1989201

Cited by 16 publications

(8 citation statements)

References 120 publications

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“…From an evolutionary perspective, this process is especially important in humans, where expansion of retrotransposition of non-coding repetitive elements -especially alu repeats -has markedly increased the amount of endogenous dsRNA within cells. 101 The importance of the immune-dampening effect of ADAR1p150 is demonstrated in loss of function mutations which result in Aicardi Goutieres Syndrome, an infantile inflammatory encephalopathy which can also cause striatal necrosis, a brain structure implicated in PD. 102 ADAR1 has two major isoforms, with the p110 exclusively found in the nucleus and the p150 being largely cytoplasmic.…”

Section: Discussionmentioning

confidence: 99%

Alpha-synuclein aggregates trigger anti-viral immune pathways and RNA editing in human astrocytes

D’Sa,

Choi,

Wagen

et al. 2024

Preprint

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Parkinson's disease is a neurodegenerative disease characterised by a proteinopathy with marked astrogliosis. To investigate how a proteinopathy may induce a reactive astrocyte state, and the consequence of reactive astrocytic states on neurons, we generated hiPSC-derived astrocytes, neurons and co-cultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory state associated with TLR activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions, and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to upregulation, and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in post-mortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinson's.

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Section: Discussionmentioning

confidence: 99%

Alpha-synuclein aggregates trigger anti-viral immune pathways and RNA editing in human astrocytes

D’Sa,

Choi,

Wagen

et al. 2024

Preprint

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“…Long-read sequencing revealed that the risk haplotype of the TMEM106B locus includes an AluYb8 retrotransposon in the canonical transcript of the 3’ UTR of TMEM106B gene. Alu-based insertions are known to (dys)regulate transcription and translation of nearby genes 31,56,57 , making the AluYb8 element a candidate driver of the neurodegenerative effect associated with the TMEM106B risk haplotype. We further observed that CpG islands in the risk and protective haplotypes were differentially methylated, potentially influencing TMEM106B transcription due to differential binding affinity of RNA polymerases and regulatory elements.…”

Section: Discussionmentioning

confidence: 99%

An AluYb8 retrotransposon characterises a risk haplotype of TMEM106B associated in neurodegeneration

Salazar,

Tesi,

Knoop

et al. 2023

Preprint

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TMEM106B may play a central role in neurodegenerative diseases. Genome-wide association studies have pointed to a risk and protective haplotype in TMEM106B across different study cohorts, including frontotemporal lobar degeneration with TAR DNA binding protein inclusions (FTD-LD) and Alzheimers disease (AD). However, the exact mechanism in which the risk haplotype of TMEM106B (genetically) exerts its pathological consequence remains elusive. Based on long-read whole-genome sequencing data of 256 individuals, we identified an AluYb8 mobile element that is inserted in the 3 UTR of TMEM106B of the risk haplotype. AluYb8s are known to be active in the human population, and can consequently (dys)regulate transcription and translation of nearby genes. Here, we propose a mechanism for how TMEM106B, PGRN, TDP-43, and age interact in neurodegeneration via a negative-feedback loop that leads to a progressive decline of the endolysosomal system.

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“…Our data revealed that a significant number of RNA editing events occurred in the coding regions, followed by intron and regulative ones, also in repetitive elements, suggesting that RNA editing may control nuclear retention and alternative splicing. In mammals, canonical editing frequently occurs within Alu repeat elements, which are mammal-specific SINEs [ 72 ]. It is already known that Alu RNA mediated cytotoxicity may induce RPE cell death by apoptosis through the accumulation of P3Alu transcripts, subsequent activation of the ERK1/2 signaling pathway, and the assembly of NLRP3 inflammasome [ 73 ].…”

Section: Discussionmentioning

confidence: 99%

Epitranscriptome Analysis of Oxidative Stressed Retinal Epithelial Cells Depicted a Possible RNA Editing Landscape of Retinal Degeneration

et al. 2022

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Oxidative stress represents one of the principal causes of inherited retinal dystrophies, with many related molecular mechanisms still unknown. We investigated the posttranscriptional RNA editing landscape of human retinal pigment epithelium cells (RPE) exposed to the oxidant agent N-retinylidene-N-retinyl ethanolamine (A2E) for 1 h, 2 h, 3 h and 6 h. Using a transcriptomic approach, refined with a specific multialgorithm pipeline, 62,880 already annotated and de novo RNA editing sites within about 3000 genes were identified among all samples. Approximately 19% of these RNA editing sites were found within 3′ UTR, including sites common to all time points that were predicted to change the binding capacity of 359 miRNAs towards 9654 target genes. A2E exposure also determined significant gene expression differences in deaminase family ADAR, APOBEC and ADAT members, involved in canonical and tRNA editing events. On GO and KEGG enrichment analyses, genes that showed different RNA editing levels are mainly involved in pathways strongly linked to a possible neovascularization of retinal tissue, with induced apoptosis mediated by the ECM and surface protein altered signaling. Collectively, this work demonstrated dynamic RNA editome profiles in RPE cells for the first time and shed more light on new mechanisms at the basis of retinal degeneration.

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Alu RNA and their roles in human disease states

Cited by 16 publications

References 120 publications

Alpha-synuclein aggregates trigger anti-viral immune pathways and RNA editing in human astrocytes

Alpha-synuclein aggregates trigger anti-viral immune pathways and RNA editing in human astrocytes

An AluYb8 retrotransposon characterises a risk haplotype of TMEM106B associated in neurodegeneration

Epitranscriptome Analysis of Oxidative Stressed Retinal Epithelial Cells Depicted a Possible RNA Editing Landscape of Retinal Degeneration

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