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SUMMARY:Flying high: a Drosophila model of mammalian prion disease - Dr Ra
 ymond Bujdoso\, Department of Veterinary Medicine\, University of Cambridg
 e
DTSTART:20160106T153000Z
DTEND:20160106T163000Z
UID:TALK60309@talks.cam.ac.uk
CONTACT:Fiona Roby
DESCRIPTION:Protein mis‐folding neurodegenerative diseases arise through
  neurotoxicity induced by aggregation of host proteins. Prion diseases\, w
 hich include scrapie of sheep\, bovine spongiform encephalopathy (BSE) of 
 cattle and Creutzfeldt-Jakob disease (CJD) of humans are associated with t
 he mis‐folding of the normal host protein PrPC into a disease-specific c
 onformer PrPSc. Prion diseases are an important Paradigm for protein mis-
 ‐folding neurodegenerative conditions in general since Alzheimer’s\, P
 arkinson’s\, and motor neuron disease\, together with tauopathies\, show
  prion‐like phenomena. Collectively\, protein mis‐folding neurodegener
 ative diseases are a challenge to society because of the increasing aged h
 uman population and as a consequence of the threat to human food security 
 caused by animal prion diseases. Understanding the mechanism of neurotoxic
 ity induced by protein mis-folding and the use of tractable bioassays that
  readily detect prion infectivity will allow the design of strategies to a
 lleviate the societal burden of these conditions. \n\nThe mechanism of pri
 on-induced neurotoxicity remains to be fully defined. The essential requir
 ement for PrP expression in prion‐induced neurotoxicity may suggest the 
 neurotoxic agent is an intermediate in the conversion of PrPC to PrPSc. Al
 ternatively\, neurotoxicity may result from PrPSc interference with the no
 rmal biosynthesis and metabolism of PrPC. Knowledge in this area will be o
 f 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 re
 ports document cell cycle activity and DNA damage repair (DDR) in post mit
 otic terminally differentiated neurons during various neurodegenerative di
 seases. This is paradoxical since these are fundamental events associated 
 with dividing cells. \n\nWe have developed PrP transgenic Drosophila for u
 se as a tractable animal model to search for genetic modifiers of prion‐
 induced neurotoxicity and the cell‐to‐cell spread of mis-folded infect
 ious protein.  In doing so we have established a new bioassay for the dete
 ction of mammalian prion infectivity in samples from prion-diseased hosts.
  We have shown that prion-exposed PrP transgenic Drosophila develop a neur
 otoxic phenotype evidenced by accelerated decline in locomotor ability. Th
 is prion--‐induced fly phenotype is accompanied by accumulation of Prote
 inase K-resistant PrPSc and is transmissible to PrP transgenic flies and m
 ice. These are hallmark features of mammalian prion disease and indicate t
 hat PrP transgenic Drosophila not only detect but replicate mammalian prio
 ns. We have begun to probe the mechanism of prion‐induced neurotoxicity 
 through our novel Drosophila model of transmissible mammalian prion diseas
 e. Our whole transcriptome analysis suggests abberant cell cycle activity 
 is an early event in prion-induced neurotoxicity. These novel studies high
 light PrP transgenic Drosophila as a new animal model for mammalian prion 
 diseases and other protein mis-folding neurodegenerative conditions that s
 how prion‐like phenomena.\n
LOCATION:Lecture Theatre 1\, Department of Veterinary Medicine
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