Genetic human prion disease modelled in PrP transgenic Drosophila
Publication Date
2017-10Journal Title
Biochemical Journal
ISSN
0264-6021
Publisher
Portland Press, Ltd.
Volume
474
Issue
19
Pages
3253-3267
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Bujdoso, R., Thackray, A., & Cardova, A. (2017). Genetic human prion disease modelled in PrP transgenic Drosophila. Biochemical Journal, 474 (19), 3253-3267. https://doi.org/10.1042/BCJ20170462
Abstract
Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt–Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene $\textit{PRNP}$ and accumulation of PrP$^{Sc}$, an abnormal isomer of the normal host protein PrP$^C$, in the brain of affected individuals. PrP$^{Sc}$ is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity. This will allow identification of possible therapeutic interventions for individuals with, or at risk from, genetic human prion disease. Increasingly, $\textit{Drosophila}$ has been used to model human neurodegenerative disease. An important unanswered question is whether genetic prion disease with concomitant spontaneous prion formation can be modelled in $\textit{Drosophila}$. We have used pUAST/PhiC31-mediated site-directed mutagenesis to generate $\textit{Drosophila}$ transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in $\textit{Drosophila}$. Adult $\textit{Drosophila}$ transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrPmediated neurotoxic fly phenotype was transferable to recipient $\textit{Drosophila}$ that expressed the wild-type form of the transgene. Collectively, our novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic $\textit{Drosophila}$ and show that inherited human prion disease can be modelled in this invertebrate host.
Sponsorship
This work was supported in part by an MRC (NC3Rs) Project Grant NC/K000462/1. AC was supported by a BBSRC postgraduate studentship award (Doctoral Training Partnership Grant BB/J014540/1).
Funder references
National Centre for the Replacement Refinement and Reduction of Animals in Research (NC/K000462/1)
Biotechnology and Biological Sciences Research Council (BB/J014540/1)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1042/BCJ20170462
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266458
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.