Genetic human prion disease modelled in PrP transgenic Drosophila.

Alana M Thackray,Alzbeta Cardova,Ina Vorberg,Raymond Bujdoso,Hanna Wolf,Lydia Pradl,Walker S Jackson

doi: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 PRNP and accumulation of PrPSc, an abnormal isomer of the normal host protein PrPC, in the brain of affected individuals. PrPSc 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, 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 Drosophila. We have used pUAST/PhiC31-mediated site-directed mutagenesis to generate 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 Drosophila. Adult 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 PrP-mediated neurotoxic fly phenotype was transferable to recipient 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 Drosophila and show that inherited human prion disease can be modelled in this invertebrate host.

Highlights

Human prion diseases are a group of fatal transmissible neurodegenerative conditions that may be genetic, acquired or arise sporadically
The mouse and hamster prion protein (PrP) transgenes carried single-codon mutations that corresponded to the human PrP mutations D178N or E200K, which are associated with inherited fatal familial insomnia (FFI) and Creutzfeldt–Jakob disease (CJD), respectively [9,10,11,12]
These PrP variants contained single amino acid substitutions associated with the human prion diseases FFI and familial Creutzfeldt–Jakob disease (fCJD) [9,10,11,12]

Summary

Introduction

Human prion diseases are a group of fatal transmissible neurodegenerative conditions that may be genetic, acquired or arise sporadically. These conditions include Creutzfeldt–Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann–Sträussler–Scheinker disease (GSS), variant CJD and kuru [1]. Prion diseases are characterised by the conversion of host PrP, the prion protein, from a normal isomer PrPC into a misfolded and aggregated abnormal conformer PrPSc, which accumulates in the brain of affected individuals [2]. Human prion diseases are transmissible, both within the species and to experimental hosts [3]. Expression of PrPC and its conversion into PrPSc are considered necessary for prion-induced neurodegeneration [5,6,7,8]

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Conclusion