X/Partial The Neuropathology Core (NP Core) is a component of the DeArmond Neuropathology Research Laboratory (NRL). NP Core directed by S. DeArmond is part of a remarkably productive collaboration with Stanley Prusiner for the past 24 years. The NP Core is particularly enthusiastic about this PPG proposal because of the results of a drug trial recently completed by the NRL in which PrPSc formation, axonal transport of PrPSc and dendrite degeneration were prevented by oral doses of a y-secretase inhibitor plus quinacrine. Residual PrPSc remained in brain regions that were the first to become infected by inoculation with prions and had accumulated high levels of PrPSc before treatment was begun. Such sites were niduses for restart of PrPSc formation. The NP Core will fulfill three basic functions: First, it will perform full autopsies on CJD patients and related controls. The basic goals are to verify the diagnosis and the immediate cause of death, and to dissect samples from the CNS, muscle, visceral organs and other sites as needed in Project 3. Second, quantitative morphological and neurochemical analysis of dissected brain regions during the course of CJD and other human prion diseases transmitted to guinea pigs and transgenic (Tg) mice will correlate the kinetics of PrPSc formation and accumulation in each brain region with the vacuolation, dendrite and presynaptic bouton degeneration;reactive astrocytic gliosis;activation of microglia;and nerve cell loss. These data will be correlated with non-invasive tests for PrPSc in blood and other systemic sites. The rodent models of human prion diseases will also allow us to test whether non-invasive peripheral measurements of abnormal PrPs or other proteins predict and correlate well with beneficial effects of emerging treatments of prion diseases that clear PrPSc from the brain and prevent neurodegeneration. Third, neuropathological verification of prion disease in hamsters, wild-type mice and Tg mice will be performed for Projects 1 and 2, which focus on the structure of PrPSc.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG002132-33
Application #
8429420
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
$204,087
Indirect Cost
$67,146
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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