Prion disease is characterized by neurodegeneration, prion protein (PrP) conformational change, and prion infectivity. Although the physical nature of infectious agent is still debated, compelling evidence favors the prion hypothesis, which postulates that the conversion from ?-helical-rich PrPC to ?-sheet-rich and protease-resistant PrPSc conformation is central to prion infectivity. Recent studies suggest a key role of other physiological factor(s) in facilitating PrP conversion and generation of prion infectivity. As a GPI-anchored protein, PrP is constantly exposed to the environment of membrane lipids and a PrP-lipid interaction has been demonstrated. The PrP binding to anionic lipids results in PrP conformational change and an alteration in lipid membrane permeability. Under an environment reminiscent of physiological conditions, the anionic lipid-PrP interaction converts a significant portion of full-length recombinant PrP into a conformation with increased ?-sheet content and a PrPSc-like proteinase K resistant pattern. Moreover, the biological relevance of PrP-lipid interaction is indicated by the influence of disease-associated mutation and the many characteristics shared by lipid-induced PrP conversion and PrPSc propagation. We propose the following studies to elucidate the contributions from lipid membrane to the pathogenesis of prion disease.
In Aim 1, the pathophysiological significance of PrP-lipid interaction will be determined using our established in vitro assays to dissect the interaction between PrP and lipid. In addition, the influence of disease-associated PrP mutations on PrP-lipid interaction will be analyzed.
In Aim 2, biochemical and animal studies will be used to determine the relationship among lipids, lipid induced PrP conformation and the self-perpetuating characteristic of prion.
In Aim 3, the importance of non-raft localized PrP to prion infection-caused pathogenic changes will be studied using a novel transgenic mouse approach. We anticipate that our proposed studies will provide us with insights into the pathogenesis of prion disease and form the basis for developing rational therapeutic and prophylactic strategies. Results from these studies may also be relevant to other neurodegenerative disorders such as Alzheimer and Parkinson's diseases, in which protein-lipid membrane interactions have been proposed as a common pathogenic process. Prion diseases are a group of infectious neurodegenerative diseases. Our goal of this proposal is to understand how the pathogenic changes occur in prion disease. This knowledge will form the basis for developing rationale preventive and therapeutic approaches against these devastating and incurable dieseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060729-05
Application #
8282853
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2008-07-15
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$321,563
Indirect Cost
$107,188
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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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
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