Prion is a protein-based infectious agent that causes a group of neurodegenerative disorders known as transmissible spongiform encephalopathies (or prion diseases). Despite years of researches, the molecular mechanism of prion transmission remains unclear. The recently developed protein misfolding cyclic amplification (PMCA) protocol for generating highly infectious prions from bacterially expressed recombinant prion protein in the presence of well-defined cofactors offers unique opportunities to probe the molecular basis of prion transmission. In this multiple PI application, we propose to use an integrated approach combining generation of recombinant prions in vitro, animal bioassay, and biophysical/structural characterization to (i) elucidate the role of lipids in prion infectivity, (i) rigorously test the hypothesis that a strong prion transmission barrier can be abrogated by serial adaptive conformational changes, and (iii) establish a novel recombinant prion propagation protocol to generate large quantities of infectious prions and, thus, facilitate future structural studies at a higher resolution level. These studies, which integrate structural and biological characterization of recombinant prions, are expected to provide valuable insights into the mechanism of prion transmission. Moreover, given the recent discoveries of a "prion-like" propagation of ordered protein aggregates in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, the findings from our studies should also have important implications for understanding the pathogenic process in these more common neurodegenerative diseases.

Public Health Relevance

Prion diseases are a group of transmissible neurodegenerative diseases affecting both human and animals. The outbreak of bovine spongiform encephalopathies (BSE) and the subsequent cross species prion transmission to humans to cause variant Creutzfeldt-Jakob Disease (vCJD) underscore the importance of understanding the mechanism of prion transmission. The studies in this application are designed to gain insight into the molecular basis for prion transmission and the barrier for prion transmission across species, which is highly relevant to human health.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
7R01NS060729-07
Application #
8681554
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Van Andel Research Institute
Department
Type
DUNS #
City
Grand Rapids
State
MI
Country
United States
Zip Code
49503
Zhang, Yi; Wang, Fei; Wang, Xinhe et al. (2014) Comparison of 2 synthetically generated recombinant prions. Prion 8:
Wang, Fei; Ma, Jiyan (2013) Role of lipid in forming an infectious prion? Acta Biochim Biophys Sin (Shanghai) 45:485-93
Wang, Fei; Zhang, Zhihong; Wang, Xinhe et al. (2012) Genetic informational RNA is not required for recombinant prion infectivity. J Virol 86:1874-6
Ma, Jiyan (2012) The role of cofactors in prion propagation and infectivity. PLoS Pathog 8:e1002589
Wang, Fei; Yin, Shaoman; Wang, Xinhe et al. (2010) Role of the highly conserved middle region of prion protein (PrP) in PrP-lipid interaction. Biochemistry 49:8169-76
Wang, Fei; Wang, Xinhe; Yuan, Chong-Gang et al. (2010) Generating a prion with bacterially expressed recombinant prion protein. Science 327:1132-5
Wang, Xinhe; Bowers, Stephanie L; Wang, Fei et al. (2009) Cytoplasmic prion protein induces forebrain neurotoxicity. Biochim Biophys Acta 1792:555-63