Abstract

Protein mis‐folding neurodegenerative diseases arise through neurotoxicity induced by aggregation of host proteins. Prion diseases, which include scrapie of sheep, bovine spongiform encephalopathy (BSE) of cattle and Creutzfeldt-Jakob disease (CJD) of humans are associated with the mis‐folding of the normal host protein PrPC into a disease-specific conformer PrPSc. Prion diseases are an important Paradigm for protein mis-‐folding neurodegenerative conditions in general since Alzheimer’s, Parkinson’s, and motor neuron disease, together with tauopathies, show prion‐like phenomena. Collectively, protein mis‐folding neurodegenerative diseases are a challenge to society because of the increasing aged human population and as a consequence of the threat to human food security caused by animal prion diseases. Understanding the mechanism of neurotoxicity induced by protein mis-folding and the use of tractable bioassays that readily detect prion infectivity will allow the design of strategies to alleviate the societal burden of these conditions.

The mechanism of prion-induced neurotoxicity remains to be fully defined. The essential requirement for PrP expression in prion‐induced neurotoxicity may suggest the neurotoxic agent is an intermediate in the conversion of PrPC to PrPSc. Alternatively, neurotoxicity may result from PrPSc interference with the normal biosynthesis and metabolism of PrPC. Knowledge in this area will be of fundamental importance to the understanding of prion biology per se and facilitate the search for early acting genetic modifiers of the neurotoxic processes in protein mis‐folding conditions. An increasing number of reports document cell cycle activity and DNA damage repair (DDR) in post mitotic terminally differentiated neurons during various neurodegenerative diseases. This is paradoxical since these are fundamental events associated with dividing cells.

We have developed PrP transgenic Drosophila for use as a tractable animal model to search for genetic modifiers of prion‐induced neurotoxicity and the cell‐to‐cell spread of mis-folded infectious protein. In doing so we have established a new bioassay for the detection of mammalian prion infectivity in samples from prion-diseased hosts. We have shown that prion-exposed PrP transgenic Drosophila develop a neurotoxic phenotype evidenced by accelerated decline in locomotor ability. This prion—‐induced fly phenotype is accompanied by accumulation of Proteinase K-resistant PrPSc and is transmissible to PrP transgenic flies and mice. These are hallmark features of mammalian prion disease and indicate that PrP transgenic Drosophila not only detect but replicate mammalian prions. We have begun to probe the mechanism of prion‐induced neurotoxicity through our novel Drosophila model of transmissible mammalian prion disease. Our whole transcriptome analysis suggests abberant cell cycle activity is an early event in prion-induced neurotoxicity. These novel studies highlight PrP transgenic Drosophila as a new animal model for mammalian prion diseases and other protein mis-folding neurodegenerative conditions that show prion‐like phenomena.