Drosophila models of oculopharyngeal muscular dystrophy (OPMD) included in study seeking therapeutic strategies for treating prion diseases

Neurotherapeutics. 2021 Feb 2. doi: 10.1007/s13311-020-00992-6

Anti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation

Bamia A, Sinane M, Naït-Saïdi R, Dhiab J, Keruzoré M, Nguyen PH, Bertho A, Soubigou F, Halliez S, Blondel M, Trollet C, Simonelig M, Friocourt G, Béringue V, Bihel F, Voisset C

From the abstract: Prion diseases are caused by the propagation of PrPSc, the pathological conformation of the PrPC prion protein ... and no therapeutic solution is currently available. We thus sought to identify new anti-prion molecules and found that flunarizine inhibited PrPSc propagation in cell culture and significantly prolonged survival of prion-infected mice. Using an in silico therapeutic repositioning approach based on similarities with flunarizine chemical structure, we tested azelastine, duloxetine, ebastine, loperamide and metixene and showed that they all have an anti-prion activity. ... Strikingly, some of these drugs were also able to alleviate phenotypes due to PABPN1 nuclear aggregation in cell and Drosophila models of oculopharyngeal muscular dystrophy (OPMD). These data emphasize the therapeutic potential of anti-PFAR drugs for neurodegenerative and neuromuscular proteinopathies.

DOI: 10.1007/s13311-020-00992-6
PMID: 33533011

Discussion of Drosophila-based bioassay of prion infectivity

Thackray AM, Andréoletti O, Bujdoso R. The use of PrP transgenic Drosophila to replace and reduce vertebrate hosts in the bioassay of mammalian prion infectivity. F1000Res. 2018 May 15;7:595. PMID: 29946445; PMCID: PMC5998032.

The abstract: "Prion diseases are fatal neurodegenerative conditions of humans and vertebrate species. The transmissible prion agent is a novel infectious particle composed principally of PrP Sc, an abnormal isomer of the normal host protein PrP C. The only reliable method to detect mammalian prion infectivity is by bioassay, invariably in a vertebrate host. The current prion bioassays typically involve intracerebral or peripheral inoculation of test material into the experimental host and subsequent euthanasia when clinical signs of terminal prion disease become evident. It may be months or years before the onset of clinical disease becomes evident and a pre-determined clinical end-point is reached. Consequently, bioassay of prion infectivity in vertebrate species is cumbersome, time consuming, expensive, and increasingly open to ethical debate because these animals are subjected to terminal neurodegenerative disease. Prions are a significant risk to public health through the potential for zoonotic transmission of animal prion diseases. Attention has focussed on the measurement of prion infectivity in different tissues and blood from prion-infected individuals in order to determine the distribution of infectious prions in diseased hosts. New animal models are required in order to replace or reduce, where possible, the dependency on the use of vertebrate species, including the 'gold standard' mouse prion bioassay, to assess prion infectivity levels. Here we highlight the development of a Drosophila-based prion bioassay, a highly sensitive and rapid invertebrate animal system that can efficiently detect mammalian prions. This novel invertebrate model system will be of considerable interest to biologists who perform prion bioassays as it will promote reduction and replacement in the number of sentient animals currently used for this purpose. This article is a composite of previous methods that provides an overview of the methodology of the model and discusses the experimental data to promote its viability for use instead of more sentient hosts."

Review--flies and prion disease

Bujdoso R, Landgraf M, Jackson WS, Thackray AM. Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response. World J Virol. 2015 Aug 12;4(3):188-97. PMID:
26279981; PMCID: PMC4534811.

From the abstract: "Protein misfolding neurodegenerative diseases arise through neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, motor neuron disease, tauopathies and prion diseases. ... Prion diseases are an important paradigm for neurodegenerative conditions in general ... Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases ... In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease."

Prion protein study includes fly assay

Robinson SW, Nugent ML, Dinsdale D, Steinert JR. Prion protein facilitates synaptic vesicle release by enhancing release probability. Hum Mol Genet. 2014 Apr 9. PMID: 24722203.

Inducible fly model of prion disease

Murali A, Maue RA, Dolph PJ. Reversible symptoms and clearance of mutant prion protein in an inducible model of a genetic prion disease in Drosophila melanogaster. Neurobiol Dis. 2014 Mar 28. pii: S0969-9961(14)00074-6. PMID: 24686303.

Inducers of hsp70 and prion disease in fly model

Zhang Y, Casas-Tinto S, Rincon-Limas DE, Fernandez-Funez P. Combined pharmacological induction of hsp70 suppresses prion protein neurotoxicity in Drosophila. PLoS One. 2014 Feb 11;9(2):e88522. doi: 10.1371/journal.pone.0088522. PMID: 24523910; PMCID: PMC3921213.