Bioassay of prion-infected blood plasma in PrP transgenic <i>Drosophila</i>

Thackray, Alana M.; Andréoletti, Olivier; Bujdoso, Raymond

doi:10.1042/bcj20160417

Cited by 11 publications

(28 citation statements)

References 40 publications

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“…However, recent studies suggest that these models hold a potential for studying, among other aspects, prion neurotoxicity [178], infectivity [177], and testing anti-prion compounds of sporadic and inherited prion disease [56]. …”

Section: Animal Models Of Prion Disease: From Monkeys To Fliesmentioning

confidence: 99%

Prion disease: experimental models and reality

Brandner

Jaunmuktane

2017

Acta Neuropathol

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overview of the use of models of prion disease, how they have evolved alongside the scientific questions, and how advancements in technologies have pushed the boundaries of our understanding of prion biology. AbstractThe understanding of the pathogenesis and mechanisms of diseases requires a multidisciplinary approach, involving clinical observation, correlation to pathological processes, and modelling of disease mechanisms. It is an inherent challenge, and arguably impossible to generate model systems that can faithfully recapitulate all aspects of human disease. It is, therefore, important to be aware of the potentials and also the limitations of specific model systems. Model systems are usually designed to recapitulate only specific aspects of the disease, such as a pathological phenotype, a pathomechanism, or to test a hypothesis. Here, we evaluate and discuss model systems that were generated to understand clinical, pathological, genetic, biochemical, and epidemiological aspects of prion diseases. Whilst clinical research and studies on human tissue are an essential component of prion research, much of the understanding of the mechanisms governing transmission, replication, and toxicity comes from in vitro and in vivo studies. As with other neurodegenerative diseases caused by protein misfolding, the pathogenesis of prion disease is complex, full of conundra and contradictions. We will give here a historical Electronic supplementary material The online version of this article

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Section: Animal Models Of Prion Disease: From Monkeys To Fliesmentioning

confidence: 99%

Prion disease: experimental models and reality

Brandner

Jaunmuktane

2017

Acta Neuropathol

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“…Furthermore, Drosophila transgenic for hamster PrP variants generally showed a more severe neurotoxic phenotype than flies transgenic for mo3F4 FFI or mo3F4 CJD PrP. The neurotoxicity we observed in mutant PrP transgenic Drosophila is similar to that seen in ovine PrP transgenic Drosophila exposed to sheep scrapie prions [ 48 – 51 ]. We reasoned that the phenotype seen in mutant PrP transgenic Drosophila was associated with spontaneous prion formation since these flies were not exposed to a source of exogenous prion infectivity.…”

Section: Discussionmentioning

confidence: 64%

“…In addition, Drosophila have several important positive experimental advantages including a short lifespan, simple genetics and a well-characterised genome that is amenable to transgenesis [ 45 – 47 ]. We have demonstrated that transmissible mammalian prion disease can be modelled in the fly [ 48 – 51 ]. Our studies have shown that PrP transgenic Drosophila develop a neurotoxic phenotype after exposure to exogenous prions that is associated with accumulation of PrP Sc and is transmissible to PrP transgenic hosts, including mice, two crucial hallmarks of bona fide mammalian prion diseases [ 48 – 51 ].…”

Section: Introductionmentioning

confidence: 99%

“…We have demonstrated that transmissible mammalian prion disease can be modelled in the fly [ 48 – 51 ]. Our studies have shown that PrP transgenic Drosophila develop a neurotoxic phenotype after exposure to exogenous prions that is associated with accumulation of PrP Sc and is transmissible to PrP transgenic hosts, including mice, two crucial hallmarks of bona fide mammalian prion diseases [ 48 – 51 ]. These data show that Drosophila possess the cellular and molecular components required for mammalian prion replication.…”

Section: Introductionmentioning

confidence: 99%

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Genetic human prion disease modelled in PrP transgenic Drosophila

Thackray

Cardova

Wolf

et al. 2017

Biochemical Journal

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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.

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“…In fact, apart from the development of new PrP Sc detection methods for diagnosis, PMCA has permitted to detect PrP Sc in extracellular vesicles from plasma of vCJD infected mice [244], which was later confirmed by IHC [245]. Although other methods have been proposed (e.g., rapid tests based on ELISA [18,246], cellular assays using prion susceptible cells [247], or bioassay in Drosophila [248]), the worse specificity and sensitivity and difficulties associated to cell culture or fly models for standardization purposes have limited their use. Nonetheless, several laboratories and companies have developed their own methods for screening of vCJD prions in blood based on distinct procedures.…”

Section: Prp Sc In Blood According To New Detection Techniquesmentioning

confidence: 99%

Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

et al. 2020

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Transmissible spongiform encephalopathies or prion diseases are rapidly progressive neurodegenerative diseases, the clinical manifestation of which can resemble other promptly evolving neurological maladies. Therefore, the unequivocal ante-mortem diagnosis is highly challenging and was only possible by histopathological and immunohistochemical analysis of the brain at necropsy. Although surrogate biomarkers of neurological damage have become invaluable to complement clinical data and provide more accurate diagnostics at early stages, other neurodegenerative diseases show similar alterations hindering the differential diagnosis. To solve that, the detection of the pathognomonic biomarker of disease, PrP Sc , the aberrantly folded isoform of the prion protein, could be used. However, the amounts in easily accessible tissues or body fluids at pre-clinical or early clinical stages are extremely low for the standard detection methods. The solution comes from the recent development of in vitro prion propagation techniques, such as Protein Misfolding Cyclic Amplification (PMCA) and Real Time-Quaking Induced Conversion (RT-QuIC), which have been already applied to detect minute amounts of PrP Sc in different matrixes and make early diagnosis of prion diseases feasible in a near future. Herein, the most relevant tissues and body fluids in which PrP Sc has been detected in animals and humans are being reviewed, especially those in which cell-free prion propagation systems have been used with diagnostic purposes.

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Bioassay of prion-infected blood plasma in PrP transgenic Drosophila

Cited by 11 publications

References 40 publications

Prion disease: experimental models and reality

Prion disease: experimental models and reality

Genetic human prion disease modelled in PrP transgenic Drosophila

Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

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