Biochemical Properties of Highly Neuroinvasive Prion Strains

PLoS Pathogens

Jeffery W. Kelly¹  Pawel Liberski²  Margarita Trejo³  Eliezer Masliah³  Shivanjali Joshi-Barr⁴  Melanie Lucero⁴  Cyrus Bett⁴  Christina J. Sigurdson⁴ 

[1] Department of Chemistry, The Scripps Research Institute, La Jolla, California, United States of America;Department of Molecular Pathology and Neuropathology, Medical University, Lodz, Poland;Department of Neuroscience, University of California, San Diego, La Jolla, California, United States of America;Departments of Pathology and Medicine, University of California, San Diego, La Jolla, California, United States of America

关键词: Animal prion diseases;    Prion diseases;    Central nervous system;    Spleen;    Nerves;    Brain diseases;    Pathogenesis;    Creutzfeldt-Jakob disease;   

DOI  :  10.1371/journal.ppat.1002522

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Infectious prions propagate from peripheral entry sites into the central nervous system (CNS), where they cause progressive neurodegeneration that ultimately leads to death. Yet the pathogenesis of prion disease can vary dramatically depending on the strain, or conformational variant of the aberrantly folded and aggregated protein, PrPSc. Although most prion strains invade the CNS, some prion strains cannot gain entry and do not cause clinical signs of disease. The conformational basis for this remarkable variation in the pathogenesis among strains is unclear. Using mouse-adapted prion strains, here we show that highly neuroinvasive prion strains primarily form diffuse aggregates in brain and are noncongophilic, conformationally unstable in denaturing conditions, and lead to rapidly lethal disease. These neuroinvasive strains efficiently generate PrPSc over short incubation periods. In contrast, the weakly neuroinvasive prion strains form large fibrillary plaques and are stable, congophilic, and inefficiently generate PrPSc over long incubation periods. Overall, these results indicate that the most neuroinvasive prion strains are also the least stable, and support the concept that the efficient replication and unstable nature of the most rapidly converting prions may be a feature linked to their efficient spread into the CNS.

【 授权许可】

CC BY