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 PrPSc. 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.
Prions are infectious proteins that cause age-dependent neurodegeneration in humans and animals. The accumulation of an alternatively folded isoform of the prion protein (PrPSc) in the brains of humans and animals is the hallmark of the prion disorders that include Creutzfeldt-Jakob disease (CJD). The prion diseases are invariably fatal and no effective treatment exists. The successful development of a drug for CJD will have important implications for creating meaningful treatments for other age-dependent neurodegenerative disorders that include Alzheimer's disease.
| O'Brien, Connor J; Droege, Daniel G; Jiu, Alexander Y et al. (2018) Photoredox Cyanomethylation of Indoles: Catalyst Modification and Mechanism. J Org Chem 83:8926-8935 |
| Condello, Carlo; Lemmin, Thomas; Stöhr, Jan et al. (2018) Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115:E782-E791 |
| Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 135:49-63 |
| Yang, Bing; Wu, Haifan; Schnier, Paul D et al. (2018) Proximity-enhanced SuFEx chemical cross-linker for specific and multitargeting cross-linking mass spectrometry. Proc Natl Acad Sci U S A 115:11162-11167 |
| Irimata, Katherine E; Dugger, Brittany N; Wilson, Jeffrey R (2018) Impact of the Presence of Select Cardiovascular Risk Factors on Cognitive Changes among Dementia Subtypes. Curr Alzheimer Res 15:1032-1044 |
| Nick, Mimi; Wu, Yibing; Schmidt, Nathan W et al. (2018) A long-lived A? oligomer resistant to fibrillization. Biopolymers 109:e23096 |
| Woerman, Amanda L; Watts, Joel C; Aoyagi, Atsushi et al. (2018) ?-Synuclein: Multiple System Atrophy Prions. Cold Spring Harb Perspect Med 8: |
| Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) Familial Parkinson's point mutation abolishes multiple system atrophy prion replication. Proc Natl Acad Sci U S A 115:409-414 |
| Johnson, Noah R; Condello, Carlo; Guan, Shenheng et al. (2017) Evidence for sortilin modulating regional accumulation of human tau prions in transgenic mice. Proc Natl Acad Sci U S A 114:E11029-E11036 |
| 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 |
Showing the most recent 10 out of 363 publications
