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
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
Wang, Tuo; Jo, Hyunil; DeGrado, William F et al. (2017) Water Distribution, Dynamics, and Interactions with Alzheimer's ?-Amyloid Fibrils Investigated by Solid-State NMR. J Am Chem Soc 139:6242-6252
Giles, Kurt; Woerman, Amanda L; Berry, David B et al. (2017) Bioassays and Inactivation of Prions. Cold Spring Harb Perspect Biol 9:

Showing the most recent 10 out of 363 publications