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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Van Andel Research Institute
Grand Rapids
United States
Zip Code
Wang, Bing; Underwood, Rachel; Kamath, Anjali et al. (2018) 14-3-3 Proteins Reduce Cell-to-Cell Transfer and Propagation of Pathogenic ?-Synuclein. J Neurosci 38:8211-8232
Li, Qiuye; Wang, Fei; Xiao, Xiangzhu et al. (2018) Structural attributes of mammalian prion infectivity: Insights from studies with synthetic prions. J Biol Chem 293:18494-18503
Wang, Fei; Wang, Xinhe; Abskharon, Romany et al. (2018) Prion infectivity is encoded exclusively within the structure of proteinase K-resistant fragments of synthetically generated recombinant PrPSc. Acta Neuropathol Commun 6:30
Becker, Katelyn; Wang, Xinhe; Vander Stel, Kayla et al. (2018) Detecting Alpha Synuclein Seeding Activity in Formaldehyde-Fixed MSA Patient Tissue by PMCA. Mol Neurobiol 55:8728-8737
Brundin, Patrik; Ma, Jiyan; Kordower, Jeffrey H (2016) How strong is the evidence that Parkinson's disease is a prion disorder? Curr Opin Neurol 29:459-66
Abskharon, Romany; Wang, Fei; Vander Stel, Kayla J et al. (2016) The role of the unusual threonine string in the conversion of prion protein. Sci Rep 6:38877
Wang, Xinhe; McGovern, Gillian; Zhang, Yi et al. (2015) Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion. PLoS Pathog 11:e1004958
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
Miller, Michael B; Wang, Daphne W; Wang, Fei et al. (2013) Cofactor molecules induce structural transformation during infectious prion formation. Structure 21:2061-8

Showing the most recent 10 out of 20 publications