Caenorhabditis elegans as a model system 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.