In this application comprising four scientific projects and four-cores, we propose to continue our studies focused on neurodegeneration caused by human prion diseases, the most common of which is sporadic (s) CJD. Prions seem to be composed solely of PrPSc molecules, which are derived from a precursor PrPc by a poorly understood process. The studies described here are aimed at defining the structure of PrPSc, characterizing the interactions of small molecules with both PrPc and PrPSc and dissecting the molecular events governing the propagation of different human prion strains. In Project 1, we propose to study the interactions of polyoxometalates (POMs) with PrP,S c . The POM phosphotungstate anion [PW12O40] (PTA) binds specifically to PrPSc, but not to PrP . POMs are a large class of inorganic metal oxide clusters with rigid polyhedral structures displaying substantial variations in size, shape, and charge density. In Project 2, we propose to carry out fiber diffraction studies of the 55-residue MoPrP(89-143,P101L) peptide that causes inherited prion disease, a 20 mer wt PrP(106-126) peptide known to form amyloid fibrils as well as purified truncated (PrP 27-30) and full-length PrPSc, both of which are infectious in wild-type animals. In Project 3, we propose to study the prions causing sCJD. These studies are possible because our most sensitive Tg mouse line expressing chimeric human/mouse PrP succumbs to disease in ~80 days after inoculation with sCJD prions. Relatively rapid bioassays of human prions in these Tg mice make it practical to measure the titers of prions throughout brain as well as in peripheral organs and body fluids collected from dead sCJD patients. We also propose to develop guinea pig models of sCJD and variant (v) CJD. In Project 4, we propose to discover new ligands that bind to and stabilize human PrPc. We also plan to determine whether such ligands inhibit the conversion of HuPrPc into HuPrPSc. Using a virtual screening approach, large libraries of organic molecules will be docked against the known structure of HuPrPc. High-scoring compounds will be tested for binding biophysically, controlling for non-specific inhibition to which anti-amyloid inhibitors are prone. The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG002132-33
Application #
8429422
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2)
Project Start
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
33
Fiscal Year
2013
Total Cost
$288,729
Indirect Cost
$94,993
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Wan, William; Stubbs, Gerald (2014) Heterogeneous seeding of HET-s(218-289) and the mutability of prion structures. Prion 8:
Silber, B Michael; Gever, Joel R; Rao, Satish et al. (2014) Novel compounds lowering the cellular isoform of the human prion protein in cultured human cells. Bioorg Med Chem 22:1960-72
Stöhr, Jan; Condello, Carlo; Watts, Joel C et al. (2014) Distinct synthetic A? prion strains producing different amyloid deposits in bigenic mice. Proc Natl Acad Sci U S A 111:10329-34
Watts, Joel C; Giles, Kurt; Patel, Smita et al. (2014) Evidence that bank vole PrP is a universal acceptor for prions. PLoS Pathog 10:e1003990
Watts, Joel C; Prusiner, Stanley B (2014) Mouse models for studying the formation and propagation of prions. J Biol Chem 289:19841-9
Watts, Joel C; Condello, Carlo; Stöhr, Jan et al. (2014) Serial propagation of distinct strains of A? prions from Alzheimer's disease patients. Proc Natl Acad Sci U S A 111:10323-8
Wan, William; Stubbs, Gerald (2014) Fiber diffraction of the prion-forming domain HET-s(218-289) shows dehydration-induced deformation of a complex amyloid structure. Biochemistry 53:2366-70
Wan, William; Stubbs, Gerald (2014) Fungal prion HET-s as a model for structural complexity and self-propagation in prions. Proc Natl Acad Sci U S A 111:5201-6
Kurouski, Dmitry; Lu, Xuefang; Popova, Ludmila et al. (2014) Is supramolecular filament chirality the underlying cause of major morphology differences in amyloid fibrils? J Am Chem Soc 136:2302-12
Li, Zhe; Gever, Joel; Rao, Satish et al. (2013) Discovery and Preliminary SAR of Arylpiperazines as Novel, Brainpenetrant Antiprion Compounds. ACS Med Chem Lett 4:397-401

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