Self-propagating, protease-resistant, recombinant prion protein conformers with or without in vivo pathogenicity

PLoS Pathogens

Romany Abskharon¹  Kumar Sinniah¹  Xinhe Wang¹  Fei Wang¹  Suzette A. Priola²  Byron Caughey³  Krystyna Surewicz³  Kayla J. Vander Stel⁴  Takashi Yokoyama⁵  Yong-Sun Kim⁵  Morikazu Imamura⁶  Jiyan Ma⁷  Witold K. Surewicz⁷  Bradley R. Groveman⁷  Christina D. Orrú⁷ 

[1] Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, United States of America;Department of Chemistry and Biochemistry, Calvin College, Grand Rapids, Michigan, United States of America;Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States of America;Ilsong Institute of Life Science, Korea CJD Diagnostic Center, Hallym University, Anyang, Republic of Korea;National Institute of Animal Health, National Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki, Japan;National Institute of Oceanography and Fisheries (NIOF), Cairo, Egypt;Rocky Mountain Laboratories, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America

关键词: Cofactors (biochemistry);    Enzyme-linked immunoassays;    Prion diseases;    Amyloid proteins;    Immunoprecipitation;    Animal prion diseases;    Pathogenesis;    Pathogens;   

DOI  :  10.1371/journal.ppat.1006491

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Prions, characterized by self-propagating protease-resistant prion protein (PrP) conformations, are agents causing prion disease. Recent studies generated several such self-propagating protease-resistant recombinant PrP (rPrP-res) conformers. While some cause prion disease, others fail to induce any pathology. Here we showed that although distinctly different, the pathogenic and non-pathogenic rPrP-res conformers were similarly recognized by a group of conformational antibodies against prions and shared a similar guanidine hydrochloride denaturation profile, suggesting a similar overall architecture. Interestingly, two independently generated non-pathogenic rPrP-res were almost identical, indicating that the particular rPrP-res resulted from cofactor-guided PrP misfolding, rather than stochastic PrP aggregation. Consistent with the notion that cofactors influence rPrP-res conformation, the propagation of all rPrP-res formed with phosphatidylglycerol/RNA was cofactor-dependent, which is different from rPrP-res generated with a single cofactor, phosphatidylethanolamine. Unexpectedly, despite the dramatic difference in disease-causing capability, RT-QuIC assays detected large increases in seeding activity in both pathogenic and non-pathogenic rPrP-res inoculated mice, indicating that the non-pathogenic rPrP-res is not completely inert in vivo. Together, our study supported a role of cofactors in guiding PrP misfolding, indicated that relatively small structural features determine rPrP-res’ pathogenicity, and revealed that the in vivo seeding ability of rPrP-res does not necessarily result in pathogenicity.

【 授权许可】

CC BY