The presence of multiple prion strains is a great challenge to the prion hypothesis, which postulates that the variations in the pathogenic PrP conformation, PrPSc, lead to the prion strain phenomenon. Recent advance in prion field reveals a key role of other physiological factor(s) in facilitating PrP conversion and generating prion infectivity. Our recent results showed that, in the presence of proper facilitating factors, the bacterially-expressed recombinant PrP can be converted into the infectious conformation causing bona fide prion disease in animals. This discovery strongly supports the prion hypothesis, highlights the important role of facilitating factors in prion conversion, and opens new avenues for prion research. We propose to use the de novo recombinant prion formation system to study the role of facilitating factors in enciphering prion strains. We will use the in vitro PrP conversion assay, biochemical characterization, animal bioassay, and histopathological analyses to investigate the relationship among facilitating factors, the infectious prion aggregates, and the prion strain phenomenon in the following three specific aims.
In aim 1, we propose to determine whether transmission in outbred mice with a single recombinant prion preparation is capable of creating multiple prion strains.
In aim 2, we will determine whether two biochemically different recombinant prions represent two different strains.
In aim 3, we will test the hypothesis that distinct prion strains can be created in the presence of different facilitating factors. Results from these studies will provide us with insights into the molecular mechanism behind prion strain phenomenon, which is critically important in preventing cross-species transmission of these fatal neurodegenerative disorders.

Public Health Relevance

Prion diseases are a group of infectious neurodegenerative diseases affecting both human and animals. The most important issue in prion research is to prevent the potential spread of prion disease from animal to humans. Prion strain phenomenon is intimately related to the cross species transmission, and therefore, our proposed study is highly relevant to human health. Furthermore, the knowledge generated from proposed studies may also lead to new strategies against these devastating and incurable diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS071035-05
Application #
8902275
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2011-08-15
Project End
2017-07-31
Budget Start
2015-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Van Andel Research Institute
Department
Type
DUNS #
129273160
City
Grand Rapids
State
MI
Country
United States
Zip Code
49503
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
Wang, Fei; Wang, Xinhe; OrrĂº, Christina D et al. (2017) Self-propagating, protease-resistant, recombinant prion protein conformers with or without in vivo pathogenicity. PLoS Pathog 13:e1006491
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:
Miller, Michael B; Wang, Daphne W; Wang, Fei et al. (2013) Cofactor molecules induce structural transformation during infectious prion formation. Structure 21:2061-8
Zhang, Zhihong; Zhang, Yi; Wang, Fei et al. (2013) De novo generation of infectious prions with bacterially expressed recombinant prion protein. FASEB J 27:4768-75
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

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