1. Caenorhabditis elegans as a modelsystem for understanding toxicity
and propagation in prion disease
Mandler A, Woolery A, Morimoto R.
Neurodegenerative diseases present a major challenge for medicine due to the debilitating
nature of their illnesses, their occurrence worldwide, and their impact on those affected.
Prion disease, a fatal group of neurodegenerative conditions impacting mammalian
nervous systems, stems from misfolded and infectious conformational isomers of the
endogenous prion protein (PrP-C). While it has been established that accumulating PrP
aggregates (PrP-Sc) result in neurodegeneration, many details about the propagation of
PrP-Sc in an infected host remain to be elucidated. In order to better understand the
mechanisms responsible, a transgenic Caenorhabditis elegans model was created by
introducing a murine PrP-C. A transgene construct encoding a neuronally-expressed PrP-
C fused with green fluorescent protein (GFP) was created for injection into wild type
worms. Upon obtaining a transgenic PrP-C expressing worm, we will certify the correct
expression patterns, subcellular localization and low background toxicity. The validated
PrP-C model worm will then be used to study aspects of PrP-Sc toxicity by infecting
them with toxic, exogenous PrP-Sc molecules. This new reagent will be used to study the
ability of PrP-Sc proteins to convert innocuous PrP-C into the toxic PrP-Sc conformation
in an animal system. The effect this toxicity has on the health, longevity and robustness
of the worms will be analyzed. The creation of these transgenic worms will allow us to
make new discoveries not only about PrP-Sc propagation, but also about nodes of stress
regulatory crosstalk that occur in cases of PrP misfolding and the associated illness of
prion disease.