Protease-Resistant Prions Selectively Decrease Shadoo Protein

PLoS Pathogens

Abby Oehler¹  Stephen J. DeArmond²  Stanley B. Prusiner²  Joel C. Watts³  Sumita Bhardwaj³  Holger Wille³  Jan Stöhr³  Kurt Giles³ 

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

关键词: Prions;    Prion diseases;    Animal prion diseases;    Mouse models;    Brain diseases;    Hamsters;    Voles;    Sheep;   

DOI  :  10.1371/journal.ppat.1002382

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The central event in prion diseases is the conformational conversion of the cellular prion protein (PrPC) into PrPSc, a partially protease-resistant and infectious conformer. However, the mechanism by which PrPSc causes neuronal dysfunction remains poorly understood. Levels of Shadoo (Sho), a protein that resembles the flexibly disordered N-terminal domain of PrPC, were found to be reduced in the brains of mice infected with the RML strain of prions [1], implying that Sho levels may reflect the presence of PrPSc in the brain. To test this hypothesis, we examined levels of Sho during prion infection using a variety of experimental systems. Sho protein levels were decreased in the brains of mice, hamsters, voles, and sheep infected with different natural and experimental prion strains. Furthermore, Sho levels were decreased in the brains of prion-infected, transgenic mice overexpressing Sho and in infected neuroblastoma cells. Time-course experiments revealed that Sho levels were inversely proportional to levels of protease-resistant PrPSc. Membrane anchoring and the N-terminal domain of PrP both influenced the inverse relationship between Sho and PrPSc. Although increased Sho levels had no discernible effect on prion replication in mice, we conclude that Sho is the first non-PrP marker specific for prion disease. Additional studies using this paradigm may provide insight into the cellular pathways and systems subverted by PrPSc during prion disease.

【 授权许可】

CC BY