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Article: ‘Non-self’ Mutation: Double-stranded RNA elicits antiviral pathogenic response in a Drosophila model of expanded CAG repeat neurodegenerative diseases

Title‘Non-self’ Mutation: Double-stranded RNA elicits antiviral pathogenic response in a Drosophila model of expanded CAG repeat neurodegenerative diseases
Authors
Keywordsinflammation
mutation
antiviral agents
drosophila
neurodegenerative disorders
Issue Date2019
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2019, v. 28 n. 18, p. 3000-3012 How to Cite?
AbstractInflammation is activated prior to symptoms in neurodegenerative diseases, providing a plausible pathogenic mechanism. Indeed, genetic and pharmacological ablation studies in animal models of several neurodegenerative diseases demonstrate that inflammation is required for pathology. However, while there is growing evidence that inflammation-mediated pathology may be the common mechanism underlying neurodegenerative diseases, including those due to dominantly inherited expanded repeats, the proximal causal agent is unknown. Expanded CAG.CUG repeat double-stranded RNA causes inflammation-mediated pathology when expressed in Drosophila. Repeat dsRNA is recognized by Dicer-2 as a foreign or ‘non-self’ molecule triggering both antiviral RNA and RNAi pathways. Neither of the RNAi pathway cofactors R2D2 nor loquacious are necessary, indicating antiviral RNA activation. RNA modification enables avoidance of recognition as ‘non-self’ by the innate inflammatory surveillance system. Human ADAR1 edits RNA conferring ‘self’ status and when co-expressed with expanded CAG.CUG dsRNA in Drosophila the pathology is lost. Cricket Paralysis Virus protein CrPV-1A is a known antagonist of Argonaute-2 in Drosophila antiviral defense. CrPV-1A co-expression also rescues pathogenesis, confirming anti-viral-RNA response. Repeat expansion mutation therefore confers ‘non-self’ recognition of endogenous RNA, thereby providing a proximal, autoinflammatory trigger for expanded repeat neurodegenerative diseases.
Persistent Identifierhttp://hdl.handle.net/10722/271187
ISSN
2023 Impact Factor: 3.1
2023 SCImago Journal Rankings: 1.602
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorvan Eyk, CL-
dc.contributor.authorSamaraweera, SE-
dc.contributor.authorScott, A-
dc.contributor.authorWebber, DL-
dc.contributor.authorHarvey, DP-
dc.contributor.authorMecinger, O-
dc.contributor.authorO’Keefe, LV-
dc.contributor.authorCropley, JE-
dc.contributor.authorYoung, P-
dc.contributor.authorHo, J-
dc.contributor.authorSuter, C-
dc.contributor.authorRichards, RI-
dc.date.accessioned2019-06-24T01:05:02Z-
dc.date.available2019-06-24T01:05:02Z-
dc.date.issued2019-
dc.identifier.citationHuman Molecular Genetics, 2019, v. 28 n. 18, p. 3000-3012-
dc.identifier.issn0964-6906-
dc.identifier.urihttp://hdl.handle.net/10722/271187-
dc.description.abstractInflammation is activated prior to symptoms in neurodegenerative diseases, providing a plausible pathogenic mechanism. Indeed, genetic and pharmacological ablation studies in animal models of several neurodegenerative diseases demonstrate that inflammation is required for pathology. However, while there is growing evidence that inflammation-mediated pathology may be the common mechanism underlying neurodegenerative diseases, including those due to dominantly inherited expanded repeats, the proximal causal agent is unknown. Expanded CAG.CUG repeat double-stranded RNA causes inflammation-mediated pathology when expressed in Drosophila. Repeat dsRNA is recognized by Dicer-2 as a foreign or ‘non-self’ molecule triggering both antiviral RNA and RNAi pathways. Neither of the RNAi pathway cofactors R2D2 nor loquacious are necessary, indicating antiviral RNA activation. RNA modification enables avoidance of recognition as ‘non-self’ by the innate inflammatory surveillance system. Human ADAR1 edits RNA conferring ‘self’ status and when co-expressed with expanded CAG.CUG dsRNA in Drosophila the pathology is lost. Cricket Paralysis Virus protein CrPV-1A is a known antagonist of Argonaute-2 in Drosophila antiviral defense. CrPV-1A co-expression also rescues pathogenesis, confirming anti-viral-RNA response. Repeat expansion mutation therefore confers ‘non-self’ recognition of endogenous RNA, thereby providing a proximal, autoinflammatory trigger for expanded repeat neurodegenerative diseases.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/-
dc.relation.ispartofHuman Molecular Genetics-
dc.rightsPre-print: Journal Title] ©: [year] [owner as specified on the article] Published by Oxford University Press [on behalf of xxxxxx]. All rights reserved. Pre-print (Once an article is published, preprint notice should be amended to): This is an electronic version of an article published in [include the complete citation information for the final version of the Article as published in the print edition of the Journal.] Post-print: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: xxxxxxx [insert URL that the author will receive upon publication here].-
dc.subjectinflammation-
dc.subjectmutation-
dc.subjectantiviral agents-
dc.subjectdrosophila-
dc.subjectneurodegenerative disorders-
dc.title‘Non-self’ Mutation: Double-stranded RNA elicits antiviral pathogenic response in a Drosophila model of expanded CAG repeat neurodegenerative diseases-
dc.typeArticle-
dc.identifier.emailHo, J: jwkho@hku.hk-
dc.identifier.authorityHo, J=rp02436-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/hmg/ddz096-
dc.identifier.pmid31071221-
dc.identifier.scopuseid_2-s2.0-85069541185-
dc.identifier.hkuros298178-
dc.identifier.volume28-
dc.identifier.issue18-
dc.identifier.spage3000-
dc.identifier.epage3012-
dc.identifier.isiWOS:000493065000002-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl0964-6906-

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