biochemical properties of highly neuroinvasive prion strains高神经感染性朊病毒菌株的生化性质.pdfVIP

Biochemical Properties of Highly Neuroinvasive Prion Strains 1 1 1 2 3 4 Cyrus Bett , Shivanjali Joshi-Barr , Melanie Lucero , Margarita Trejo , Pawel Liberski , Jeffery W. Kelly , Eliezer Masliah2, Christina J. Sigurdson1,5* 1 Departments of Pathology and Medicine, University of California, San Diego, La Jolla, California, United States of America, 2 Department of Neuroscience, University of California, San Diego, La Jolla, California, United States of America, 3 Department of Molecular Pathology and Neuropathology, Medical University, Lodz, Poland, 4 Department of Chemistry, The Scripps Research Institute, La Jolla, California, United States of America, 5 Department of Pathology, Microbiology, and Immunology, University of California, Davis, California, United States of America Abstract 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 f