Protease-Sensitive Synthetic Prions

PLoS Pathogens

Stanley B. Prusiner¹  Christina G. Palmer²  Fred E. Cohen³  Giuseppe Legname⁴  Azucena Lemus⁴  Ilia V. Baskakov⁴  Stephen J. DeArmond⁴  Rachel Wain⁴  David W. Colby⁴  Hoang-Oanh B. Nguyen⁴ 

[1] Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, United States of America;Department of Neurology, University of California, San Francisco, California, United States of America;Department of Pathology, University of California, San Francisco, California, United States of America;Institute for Neurodegenerative Diseases, University of California, San Francisco, California, United States of America

关键词: Prions;    Prion diseases;    Animal prion diseases;    Infectious disease control;    Neuropathology;    Proteases;    Nerve fibers;    Brain diseases;   

DOI  :  10.1371/journal.ppat.1000736

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Prions arise when the cellular prion protein (PrPC) undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrPSc. Frequently, PrPSc is protease-resistant but protease-sensitive (s) prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec) PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but not recPrP monomers or oligomers, transmitted disease to transgenic mice (n = 164), denoted Tg9949 mice, that overexpress N-terminally truncated PrP. Tg9949 control mice (n = 174) did not spontaneously generate prions although they were prone to late-onset spontaneous neurological dysfunction. When synthetic prion isolates from infected Tg9949 mice were serially transmitted in the same line of mice, they exhibited sPrPSc and caused neurodegeneration. Interestingly, these protease-sensitive prions did not shorten the life span of Tg9949 mice despite causing extensive neurodegeneration. We inoculated three synthetic prion isolates into Tg4053 mice that overexpress full-length PrP; Tg4053 mice are not prone to developing spontaneous neurological dysfunction. The synthetic prion isolates caused disease in 600–750 days in Tg4053 mice, which exhibited sPrPSc. These novel synthetic prions demonstrate that conformational changes in wild-type PrP can produce mouse prions composed exclusively of sPrPSc.

【 授权许可】

CC BY