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 #
5P01AG002132-31
Application #
8215265
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
31
Fiscal Year
2011
Total Cost
$295,447
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Woerman, Amanda L; Watts, Joel C; Aoyagi, Atsushi et al. (2017) ?-Synuclein: Multiple System Atrophy Prions. Cold Spring Harb Perspect Med :
Stöhr, Jan; Wu, Haifan; Nick, Mimi et al. (2017) A 31-residue peptide induces aggregation of tau's microtubule-binding region in cells. Nat Chem 9:874-881
Lopez, T Peter; Giles, Kurt; Dugger, Brittany N et al. (2017) A novel vector for transgenesis in the rat CNS. Acta Neuropathol Commun 5:84
Lee, Myungwoon; Wang, Tuo; Makhlynets, Olga V et al. (2017) Zinc-binding structure of a catalytic amyloid from solid-state NMR. Proc Natl Acad Sci U S A 114:6191-6196
Watts, Joel C; Prusiner, Stanley B (2017) ?-Amyloid Prions and the Pathobiology of Alzheimer's Disease. Cold Spring Harb Perspect Med :
Saltzberg, Daniel J; Broughton, Howard B; Pellarin, Riccardo et al. (2017) A Residue-Resolved Bayesian Approach to Quantitative Interpretation of Hydrogen-Deuterium Exchange from Mass Spectrometry: Application to Characterizing Protein-Ligand Interactions. J Phys Chem B 121:3493-3501
Adler, C H; Beach, T G; Shill, H A et al. (2017) GBA mutations in Parkinson disease: earlier death but similar neuropathological features. Eur J Neurol 24:1363-1368
Gerkin, Richard C; Adler, Charles H; Hentz, Joseph G et al. (2017) Improved diagnosis of Parkinson's disease from a detailed olfactory phenotype. Ann Clin Transl Neurol 4:714-721
Giles, Kurt; Olson, Steven H; Prusiner, Stanley B (2017) Developing Therapeutics for PrP Prion Diseases. Cold Spring Harb Perspect Med 7:

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