Darwinian Evolution of Prions in Cell Culture

• Published in: Science (American Association for the Advancement of Science) Vol. 327; no. 5967; pp. 869 - 872
• Main Authors: Li, Jiali, Browning, Shawn, Mahal, Sukhvir P, Oelschlegel, Anja M, Weissmann, Charles
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 12.02.2010; The American Association for the Advancement of Science
• Subjects: Animals; Biological and medical sciences; Biological evolution; brain; Brain Chemistry; Cell culture; Cell culture techniques; Cell Line; Cell Line, Tumor; Cellular biology; Culture Media; Culture Media, Conditioned; Cultured cells; Darwinism; Evolution; Evolution, Molecular; Evolutionary biology; Fundamental and applied biological sciences. Psychology; Genetic mutation; Genetics of eukaryotes. Biological and molecular evolution; genome; Infections; Mice; Mice, Inbred C57BL; Microbiology; Molecular and cellular biology; mutants; Mutation; Nervous system diseases; Non conventional transmissible agents; Nucleic acids; Polysaccharides; Prion Diseases; Prions; Prions - chemistry; Prions - classification; Prions - pathogenicity; Prions - physiology; Protein Conformation; Proteins; PrPSc proteins; PrPSc Proteins - chemistry; PrPSc Proteins - classification; PrPSc Proteins - pathogenicity; swainsonine; Swainsonine - pharmacology; Amplification; Cell culture; Molecular evolution; Prion; Mutation
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1183218

Prions are infectious proteins consisting mainly of PrPSc, a β sheet-rich conformer of the normal host protein PrPC, and occur in different strains. Strain identity is thought to be encoded by PrPSc conformation. We found that biologically cloned prion populations gradually became heterogeneous by accumulating "mutants," and selective pressures resulted in the emergence of different mutants as major constituents of the evolving population. Thus, when transferred from brain to cultured cells, "cell-adapted" prions outcompeted their "brain-adapted" counterparts, and the opposite occurred when prions were returned from cells to brain. Similarly, the inhibitor swainsonine selected for a resistant substrain, whereas, in its absence, the susceptible substrain outgrew its resistant counterpart. Prions, albeit devoid of a nucleic acid genome, are thus subject to mutation and selective amplification.