Show simple item record

dc.contributor.authorThackray, Alana M
dc.contributor.authorLam, Brian
dc.contributor.authorShahira Binti Ab Razak, Anisa
dc.contributor.authorYeo, Giles
dc.contributor.authorBujdoso, Raymond
dc.date.accessioned2020-03-31T00:32:23Z
dc.date.available2020-03-31T00:32:23Z
dc.date.issued2020-02-01
dc.identifier.issn0264-6021
dc.identifier.otherPMC7054746
dc.identifier.other32108870
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/303933
dc.description.abstractPrion diseases are fatal transmissible neurodegenerative conditions of humans and animals that arise through neurotoxicity induced by PrP misfolding. The cellular and molecular mechanisms of prion-induced neurotoxicity remain undefined. Understanding these processes will underpin therapeutic and control strategies for human and animal prion diseases, respectively. Prion diseases are difficult to study in their natural hosts and require the use of tractable animal models. Here we used RNA-Seq-based transcriptome analysis of prion-exposed Drosophila to probe the mechanism of prion-induced neurotoxicity. Adult Drosophila transgenic for pan neuronal expression of ovine PrP targeted to the plasma membrane exhibit a neurotoxic phenotype evidenced by decreased locomotor activity after exposure to ovine prions at the larval stage. Pathway analysis and quantitative PCR of genes differentially expressed in prion-infected Drosophila revealed up-regulation of cell cycle activity and DNA damage response, followed by down-regulation of eIF2 and mTOR signalling. Mitochondrial dysfunction was identified as the principal toxicity pathway in prion-exposed PrP transgenic Drosophila. The transcriptomic changes we observed were specific to PrP targeted to the plasma membrane since these prion-induced gene expression changes were not evident in similarly treated Drosophila transgenic for cytosolic pan neuronal PrP expression, or in non-transgenic control flies. Collectively, our data indicate that aberrant cell cycle activity, repression of protein synthesis and altered mitochondrial function are key events involved in prion-induced neurotoxicity, and correlate with those identified in mammalian hosts undergoing prion disease. These studies highlight the use of PrP transgenic Drosophila as a genetically well-defined tractable host to study mammalian prion biology.
dc.languageeng
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1470-8728
dc.sourcenlmid: 2984726R
dc.subjectDrosophila melanogaster
dc.subjectPrion
dc.subjectNeurodegeneration
dc.subjectTranscriptomics
dc.titleTranscriptional signature of prion-induced neurotoxicity in a Drosophila model of transmissible mammalian prion disease.
dc.typeArticle
dc.date.updated2020-03-31T00:32:23Z
prism.endingPage852
prism.issueIdentifier4
prism.publicationNameThe Biochemical journal
prism.startingPage833
prism.volume477
dc.identifier.doi10.17863/CAM.51017
rioxxterms.versionofrecord10.1042/BCJ20190872
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
pubs.funder-project-idNational Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000462/1)


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International