Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy

Khan, Aalia; Paro, Simona; McGurk, Leeanne; Sambrani, Nagraj; Hogg, Marion C.; Brindle, James; Pennetta, Giuseppa; Keegan, Liam P.; O’Connell, Mary A.

doi:10.1186/s12915-020-0747-0

Cited by 19 publications

(23 citation statements)

References 72 publications

(96 reference statements)

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“…Previous analyses have suggested that hybridization events can generate discordance between species and mitochondrial phylogenies in yeast ( Peris et al. 2017 ; De Chiara et al. 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Genomic Evidence of an Ancient East Asian Divergence Event in Wild Saccharomyces cerevisiae

Bendixsen¹,

Gettle²,

Gilchrist³

et al. 2021

Genome Biology and Evolution

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Comparative genome analyses have suggested East Asia to be the cradle of the domesticated microbe Brewer’s yeast (Saccharomyces cerevisiae), used in the food and biotechnology industry worldwide. Here, we provide seven new, high-quality long-read genomes of nondomesticated yeast strains isolated from primeval forests and other natural environments in China and Taiwan. In a comprehensive analysis of our new genome assemblies, along with other long-read Saccharomycetes genomes available, we show that the newly sequenced East Asian strains are among the closest living relatives of the ancestors of the global diversity of Brewer’s yeast, confirming predictions made from short-read genomic data. Three of these strains (termed the East Asian Clade IX Complex here) share a recent ancestry and evolutionary history suggesting an early divergence from other S. cerevisiae strains before the larger radiation of the species, and prior to its domestication. Our genomic analyses reveal that the wild East Asian strains contain elevated levels of structural variations. The new genomic resources provided here contribute to our understanding of the natural diversity of S. cerevisiae, expand the intraspecific genetic variation found in this heavily domesticated microbe, and provide a foundation for understanding its origin and global colonization history.

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“…Previous analyses have suggested that hybridization events can generate discordance between species and mitochondrial phylogenies in yeast ( Peris et al. 2017 ; De Chiara et al. 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Genomic Evidence of an Ancient East Asian Divergence Event in Wild Saccharomyces cerevisiae

Bendixsen¹,

Gettle²,

Gilchrist³

et al. 2021

Genome Biology and Evolution

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“…An additional way whereby innate immune induction could contribute to all Adar 5G1 mutant phenotypes is described in a related manuscript 50 . That manuscript shows that reduced autophagy in Adar 5G1 leads to synaptic defects with aberrant accumulation of neurotransmitter synaptic vesicles and associated proteins.…”

Section: Discussionmentioning

confidence: 99%

Adar RNA editing-dependent and -independent effects are required for brain and innate immune functions in Drosophila

et al. 2020

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ADAR RNA editing enzymes are high-affinity dsRNA-binding proteins that deaminate adenosines to inosines in pre-mRNA hairpins and also exert editing-independent effects. We generated a Drosophila Adar E374A mutant strain encoding a catalytically inactive Adar with CRISPR/Cas9. We demonstrate that Adar adenosine deamination activity is necessary for normal locomotion and prevents age-dependent neurodegeneration. The catalytically inactive protein, when expressed at a higher than physiological level, can rescue neurodegeneration in Adar mutants, suggesting also editing-independent effects. Furthermore, loss of Adar RNA editing activity leads to innate immune induction, indicating that Drosophila Adar, despite being the homolog of mammalian ADAR2, also has functions similar to mammalian ADAR1. The innate immune induction in fly Adar mutants is suppressed by silencing of Dicer-2, which has a RNA helicase domain similar to MDA5 that senses unedited dsRNAs in mammalian Adar1 mutants. Our work demonstrates that the single Adar enzyme in Drosophila unexpectedly has dual functions.

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“…Later, ADAR1 was lost in some metazoans, such as arthropods, including Drosophila [45]; Drosophila Adar site-specifically edits many central nervous system (CNS) transcripts and is an orthologue of mammalian ADAR2, which has no known effect on innate immunity and instead site-specifically edits transcripts encoding glutamate receptor subunits to recode them [45]. Adar 5G1 -null mutant flies have severe locomotion defects and aberrant neurotransmitter synaptic vesicle accumulation and develop age-dependent neurodegeneration [46,47]. Unexpectedly, the Drosophila Adar 5G1 mutant also has an aberrant induction of innate immune transcripts caused by loss of RNA editing.…”

Section: Other Adar1 Effects On Innate Immunitymentioning

confidence: 99%

ADAR RNA Modifications, the Epitranscriptome and Innate Immunity

Quin

Sedmik

Vukić

et al. 2021

Trends in Biochemical Sciences

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Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosineto-inosine deamination, cause a viral infection mimic syndrome, a congenital encephalitis with aberrant interferon induction. These Aicardi-Goutières syndrome 6 mutations affect adenosine deaminase acting on RNA 1 (ADAR1), which generates inosines in endogenous double-stranded (ds)RNA. The inosine base alters dsRNA structure to prevent aberrant activation of antiviral cytosolic helicase RIG-I-like receptors. We review how effects of inosines, ADARs, and other modified bases have been shown to be important in innate immunity and cancer. The Epitranscriptome, ADARs, and InosinesModified bases act as marks of self-RNA to reduce innate immune responses to endogenous cellular RNA. Over 170 different types of enzymatic RNA modifications are known to occur in stable RNAs, such as tRNAs and rRNAs, where many contribute to their high stabilities and optimise the activities of these RNAs [1]. Different types of base modifications have also been found in eukaryotic mRNAs, where they are called epitranscriptomic (see Glossary) modifications [2]. Base modifications that have been detected in mRNA include adenosine to inosine (A-to-I) deamination and cytosine to uracil (C-to-U) deamination, N 6 -methyladenosine (m 6 A), N 1 -methyladenosine (m 1 A), 5-methylcytosine (5mC), and pseudouridine (ψ), as well as ribose 2′O-methyl [1]. Many of these modifications affect innate immune responses to RNA [3-6], and understanding these effects has been critical for development of mRNA therapeutics and vaccines [7].We focus here on A-to-I deamination, which was one of the first RNA base modifications identified; it is abundant in tRNAs and plays a key role in tRNA wobble decoding. It was also one of the first epitranscriptomic mRNA modifications identified, because it is readily detected by RNA sequencing (RNA-seq). A-to-I RNA modification/editing found in mRNAs is catalysed by adenosine deaminases acting on RNAs (ADARs). In mammals, there are three ADAR family members: ADAR1 and ADAR2 deaminate double-stranded (ds)RNA, whereas ADAR3 is enzymatically inactive (for review, see [8]). This review focuses primarily on ADAR1, summarising the evidence for its role in innate immunity (Figure 1) and how this role of ADARs is evolutionarily conserved. We also aim to clarify how and when A-to-I conversion acts as an epitranscriptomic RNA modification versus the rarer cases where it acts as an RNA editing event. This RNA modification role of the ADARs has been, and will continue to be, a trailblazer for understanding epitranscriptomic roles of many types of RNA modifications. Finally, we also summarise human diseases and SNPs associated with ADAR1 and the roles of ADAR1 in tumour immunity. ADAR1, the Inosinome, and Effects on Three Levels ADAR1The three ADARs are composed of two or more dsRNA-binding domains (dsRBDs) followed ...

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Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy

Cited by 19 publications

References 72 publications

Genomic Evidence of an Ancient East Asian Divergence Event in Wild Saccharomyces cerevisiae

Genomic Evidence of an Ancient East Asian Divergence Event in Wild Saccharomyces cerevisiae

Adar RNA editing-dependent and -independent effects are required for brain and innate immune functions in Drosophila

ADAR RNA Modifications, the Epitranscriptome and Innate Immunity

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