Dr. Jiali Li (Candidate for the Macromolecular Assemblies position)
Scripps Florida Research Institute
Monday, December 5, 2011 - 15:00 to 16:00
1116-1118 Marcus Nanotechnology Bldg
Evolution of Prions in Cell Culture
Prions, the pathogens causing transmissible spongiform encephalopathies, are unique in that they consist mainly of multimers of PrPSc, a conformer of the host-encoded protein PrPC. Prions occur in the form of diverse strains, which differ in various phenotypic properties but whose PrPSc has the same amino acid sequence. It is believed that strain-ness is encoded by different conformations of PrPSc. We found that prion populations exhibit features of Darwinian evolution in that they are subject to “mutations” (believed to be due to conformational changes) that give rise to heterogeneity and allow selective amplification of prions in different environments. We have shown that a biologically cloned prion strain, 22L, when transferred from brain to cultured cells, gives rise to a population with changed properties, and when returned to brain, recovers the original properties. Moreover, when propagated in cell culture in the presence of an inhibitory drug, the prion population acquires resistance to it. This is quite remarkable, considering that bacteria and viruses acquire drug resistance as a consequence of random mutations in their genetic material, whereas prions do not contain informational nucleic acids. These findings indicate that targeting PrPSc directly for design a therapeutic molecule may lead to emergence of drug resistant strains, therefore impact on the strategies envisaged for therapeutic approaches to prion disease.