Loss of APOBEC1 RNA-editing function in microglia exacerbates age-related CNS pathophysiology

Cole, Daniel C.; Chung, Youngcheul; Gagnidze, Khatuna; Hajdarovic, Kaitlyn H.; Rayon-Estrada, Violeta; Harjanto, Dewi; Bigio, Benedetta; Gal-Toth, Judit; Milner, Teresa A.; McEwen, Bruce S.; Papavasiliou, F. Nina; Bulloch, Karen

doi:10.1073/pnas.1710493114

Cited by 40 publications

(42 citation statements)

References 55 publications

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“…While we observed no gross defects in liver or intestinal development in Rbm47 IKO , Rbm47 LKO , or the corresponding double knockout lines (i.e., AR IKO and AR LKO mice), we are currently examining in more detail the possibilities of other growth-related and metabolic phenotypes. As a final comment, we recognize that the current findings are limited to the tissue-specific impact of A1CF and of RBM47 within the liver and small intestine but we certainly acknowledge the importance of APOBEC1 dependent C-to-U RNA editing activity in other cell types as revealed by recent studies in microglia and monocytes derived from Apobec1 −/− mice (Cole et al 2017;Rayon-Estrada et al 2017). We envision future studies utilizing a range of other cell-specific Cre drivers to elucidate the role of RBM47 in those contexts also.…”

Section: Discussionmentioning

confidence: 81%

Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver

Blanc

Xie

Kennedy

et al. 2018

RNA

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Mammalian C to U RNA is mediated by APOBEC1, the catalytic deaminase, together with RNA binding cofactors (including A1CF and RBM47) whose relative physiological requirements are unresolved. Although A1CF complements APOBEC1 for in vitro RNA editing, A1cf -/mice exhibited no change in apolipoproteinB (apoB) RNA editing, while Rbm47 mutant mice exhibited impaired intestinal RNA editing of apoB as well as other targets. Here we examined the role of A1CF and RBM47 in adult mouse liver and intestine, following deletion of either one or both gene products and also following forced (liver or intestinal) transgenic A1CF expression. There were minimal changes in hepatic and intestinal apoB RNA editing in A1cf -/mice and no changes in either liver-or intestine-specific A1CF transgenic mice. Rbm47 liver-specific knockout (Rbm47 LKO ) mice demonstrated reduced editing in a subset (11 of 20) of RNA targets, including apoB. By contrast, apoB RNA editing was virtually eliminated (<6% activity) in intestine-specific (Rbm47 IKO ) mice with only five of 53 targets exhibiting C-to-U RNA editing. Double knockout of A1cf and Rbm47 in liver (AR LKO ) eliminated apoB RNA editing and reduced editing in the majority of other targets, with no changes following adenoviral APOBEC1 administration. Intestinal double knockout mice (AR IKO ) demonstrated further reduced editing (<10% activity) in four of five of the residual APOBEC1 targets identified in AR IKO mice. These data suggest that A1CF and RBM47 each function independently, yet interact in a tissue-specific manner, to regulate the activity and site selection of APOBEC1 dependent C-to-U RNA editing.

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Section: Discussionmentioning

confidence: 81%

Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver

Blanc

Xie

Kennedy

et al. 2018

RNA

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“…Cognitive impairment in AD occurs before the appearance of amyloid plaques and neurofibrillary tangles, although the soluble Aβ oligomers and hyperphosphorylated tau damage cognitive function (Lesne et al, ; Pater, ). Many studies have highlighted chronic neuroinflammation as a dedicator to the pathogenesis of AD (Cole et al, ; Mesquita et al, ). For instance, neuroinflammation induced by the repeated administration of LPS led to an accumulation of Aβ 42 in the hippocampus and cerebral cortex of an outbred ICR mouse (Lee et al, ).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide exposure during late embryogenesis triggers and drives Alzheimer‐like behavioral and neuropathological changes in CD‐1 mice

et al. 2020

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Introduction Infections could contribute to Alzheimer's disease (AD) neuropathology in human. However, experimental evidence for a causal relationship between infections during the prenatal phase and the onset of AD is lacking. Methods CD‐1 mothers were intraperitoneally received lipopolysaccharide (LPS) with two doses (25 and 50 μg/kg) or normal saline every day during gestational days 15–17. A battery of behavioral tasks was used to assess the species‐typical behavior, sensorimotor capacity, anxiety, locomotor activity, recognition memory, and spatial learning and memory in 1‐, 6‐, 12‐, 18‐, and 22‐month‐old offspring mice. An immunohistochemical technology was performed to detect neuropathological indicators consisting of amyloid‐β (Aβ), phosphorylated tau (p‐tau), and glial fibrillary acidic protein (GFAP) in the hippocampus. Results Compared to the same‐aged controls, LPS‐treated offspring had similar behavioral abilities and the levels of Aβ42, p‐tau, and GFAP at 1 and 6 months old. From 12 months onward, LPS‐treated offspring gradually showed decreased species‐typical behavior, sensorimotor ability, locomotor activity, recognition memory, and spatial learning and memory, and increased anxieties and the levels of Aβ42, p‐tau, and GFAP relative to the same‐aged controls. Moreover, this damage effect (especially cognitive decline) persistently progressed onwards. The changes in these neuropathological indicators significantly correlated with impaired spatial learning and memory. Conclusions Prenatal exposure to low doses of LPS caused AD‐related features including behavioral and neuropathological changes from midlife to senectitude.

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“…In contrast to APOBEC1, APOBEC3A and 3G are expressed in most tissues (Figure 2a), but APOBEC1 is the most well characterized isoform of the AID/APOBEC family [50]. Loss of APOBEC1 does not alter embryonic development but it impairs lipoprotein metabolism by editing apolipoprotein B (apoB) RNA and it affects neurological function [48][49][50][51]. In contrast to information collected from DICE database (Figure 2b), the APOBEC1 deaminase was reported to be significantly expressed in immune cells, where it exerts RNA editing activity on 3 -UTRs of numerous mRNAs [48,50,52].…”

Section: Aid/apobecmentioning

confidence: 99%

Deciphering miRNAs’ Action through miRNA Editing

Sousa

Gjorgjieva

Dolicka

et al. 2019

IJMS

608

343

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MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation. The outcome of a myriad of physiological processes and pathologies, including cancer, cardiovascular and metabolic diseases, relies highly on miRNAs. However, deciphering the precise roles of specific miRNAs in these pathophysiological contexts is challenging due to the high levels of complexity of their actions. Indeed, regulation of mRNA expression by miRNAs is frequently cell/organ specific; highly dependent on the stress and metabolic status of the organism; and often poorly correlated with miRNA expression levels. Such biological features of miRNAs suggest that various regulatory mechanisms control not only their expression, but also their activity and/or bioavailability. Several mechanisms have been described to modulate miRNA action, including genetic polymorphisms, methylation of miRNA promoters, asymmetric miRNA strand selection, interactions with RNA-binding proteins (RBPs) or other coding/non-coding RNAs. Moreover, nucleotide modifications (A-to-I or C-to-U) within the miRNA sequences at different stages of their maturation are also critical for their functionality. This regulatory mechanism called "RNA editing" involves specific enzymes of the adenosine/cytidine deaminase family, which trigger single nucleotide changes in primary miRNAs. These nucleotide modifications greatly influence a miRNA's stability, maturation and activity by changing its specificity towards target mRNAs. Understanding how editing events impact miRNA's ability to regulate stress responses in cells and organs, or the development of specific pathologies, e.g., metabolic diseases or cancer, should not only deepen our knowledge of molecular mechanisms underlying complex diseases, but can also facilitate the design of new therapeutic approaches based on miRNA targeting. Herein, we will discuss the current knowledge on miRNA editing and how this mechanism regulates miRNA biogenesis and activity.

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Loss of APOBEC1 RNA-editing function in microglia exacerbates age-related CNS pathophysiology

Cited by 40 publications

References 55 publications

Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver

Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver

Lipopolysaccharide exposure during late embryogenesis triggers and drives Alzheimer‐like behavioral and neuropathological changes in CD‐1 mice

Deciphering miRNAs’ Action through miRNA Editing

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