Project 1 Prusiner There is increasing evidence from both cell culture and animal models that both the A peptide and the tau protein become self-propagating in Alzheimer's disease (AD), initiating a cascade of neurodegeneration that spreads throughout the brain, indicating that A and tau are prions. Thus, the molecular events underlying the pathogenesis of AD and tauopathies are reminiscent of Creutzfeldt-Jakob disease (CJD), in which the misfolding of the prion protein (PrP) into a self-templating isoform termed PrPSc initiates disease. However, to better understanding the structural and biochemical properties of self-propagating protein aggregates in AD requires the creation of cellular and animal bioassays capable of rapidly ascertaining the presence of these prions. We propose to study three different human prions composed of PrPSc, A or tau, each of which cause age-dependent neurodegeneration. In these studies, we will take advantage of new paradigms that allows us to monitor disease progression and to diagnose neurodegeneration in living mice, in addition to novel cellular assays, greatly accelerating research efforts.
In Aim 1 we will build on our recent observation that Tg(APP23) can propagate different A strains. We propose to identify A strain diversity from both natural and synthetic sources, both by bioassay and in cell culture. We also plan to generate new transgenic rat models.
In Aim 2 we attempt to create a better models of sporadic and genetic human prion diseases by a combination of cell culture and transgenic mouse studies, based on studies demonstrating that bank vole PrP can faithfully propagate human prion strains.
In Aim 3, we will investigate a cell model of intracellular tau aggregation to develop a cellular bioassay for tau prions using confocal fluorescence microscopy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG002132-37
Application #
9457299
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
37
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Giles, Kurt; Woerman, Amanda L; Berry, David B et al. (2017) Bioassays and Inactivation of Prions. Cold Spring Harb Perspect Biol 9:
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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