Neuropathology Cores directed by Dr. DeArmond have been part of Stanley Prusiner PPGs for the past 25 years. The overall goal has been to test the hypothesis that emerged from Dr. DeArmond's early correlative kinefic studies of PrP [Sc] neurochemistry, PrP[Sc] immunohistochemistry, and neuropathological analysis during the course of prion diseases, which stated that formation and accumulation of PrP[Sc] in neurons are the cause ofthe clinically relevant neuropathological changes. All of our evidence today suggests that neurodegeneration in prion diseases progresses in stereotypical sequence of pathogenic events that underlies neurological dysfunction and degenerafion in prion disease. The sequence encompasses a progression of funcfional and neuropathological changes that begin with formafion and accumulafion abnormal protease resistant PrP?*^ in neurons, proceeds rapidly to synaptic degeneration as PrP^""""""""^ accumulates in plasma membranes, and terminates in autophagic nerve cell death when PrP?? accumulates in lysosomes and autophagosomes. The main theme of this PPG's Projects is prion strains. Project 1 proposes to create multiple synthetic prions and compare their physical characteristics with their pathologic phenotype in transgenic mice. In Project 2, yeast prions Sc4 and Sc37 will be mutated to test their ability to infect mammalian cells in vitro and in vivo. Project 3 proposes to use """"""""induced neuronal cells"""""""" (iN cells) carrying mutations in genes associated with neurodegenerafion, such as APP, presenilin-1 and tau, and test whether the gene mutations predispose them for prion-like infecfion. The Neuropathology Core has all techniques and expertise to analyze the fissues provided to us. The resulfing pathologies may be novel.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010770-21
Application #
8658336
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
21
Fiscal Year
2014
Total Cost
$156,289
Indirect Cost
$55,683
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Watts, Joel C; Giles, Kurt; Saltzberg, Daniel J et al. (2016) Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions. J Virol 90:9558-9569
Watts, Joel C; Giles, Kurt; Bourkas, Matthew E C et al. (2016) Towards authentic transgenic mouse models of heritable PrP prion diseases. Acta Neuropathol 132:593-610
Ahlenius, Henrik; Chanda, Soham; Webb, Ashley E et al. (2016) FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice. Proc Natl Acad Sci U S A 113:8514-9
Dunn, Joshua G; Weissman, Jonathan S (2016) Plastid: nucleotide-resolution analysis of next-generation sequencing and genomics data. BMC Genomics 17:958
Patzke, Christopher; Acuna, Claudio; Giam, Louise R et al. (2016) Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation. J Exp Med 213:499-515
Giles, Kurt; Berry, David B; Condello, Carlo et al. (2016) Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice. J Pharmacol Exp Ther 358:537-47
Elkins, Matthew R; Wang, Tuo; Nick, Mimi et al. (2016) Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. J Am Chem Soc 138:9840-52
Lim, Kwang Hun; Dasari, Anvesh K R; Hung, Ivan et al. (2016) Solid-State NMR Studies Reveal Native-like β-Sheet Structures in Transthyretin Amyloid. Biochemistry 55:5272-8
Lim, Kwang Hun; Dasari, Anvesh K R; Hung, Ivan et al. (2016) Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR. Biochemistry 55:1941-4
Levine, Dana J; Stöhr, Jan; Falese, Lillian E et al. (2015) Mechanism of scrapie prion precipitation with phosphotungstate anions. ACS Chem Biol 10:1269-77

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