The neurodegenerative diseases include Alzheimer's, Parkinson's and prion disease, all of which are disorders of protein processing. Toward developing effective therapies for the protein processing diseases, we have focused on prion disease as a model system. The study of prion disease is advantageous since robust cell and transgenic (Tg) mouse models of disease are available. These cell and mouse systems facilitate measurements of disease progression and therapeutic intervention. Due to the commonality amongst the protein processing diseases, it is thought that lessons learnt in developing therapies for prion disease may have important implications for disorders like Alzheimer's and Parkinson's diseases that affect vastly greater numbers of people. Prion diseases are characterized by the misfolding of the cellular isoform of the prion protein, designated PrPc, to the disease causing isoform, denoted PrPSc. We have identified critical points in the replication of PrPSc that may be suitable for therapeutic intervention with small molecules. These include, expression and localization of the substrate, PrPc;subsequent conversion to PrPSc;and cellular clearance of PrPSc. In this application we propose to generate new screening procedures for compounds that might serve as therapeutics for prion diseases. Our goal is to develop robust, high throughput system (HTS) assays for PrPc, PrPSc accumulation, and PrPSc clearance. These in vitro screening systems will be complemented with new Tg mice that lack the multi-drug resistance (mdr) genes la and b and hence, can overcome problems traditionally associated with achieving substantial concentrations of test compounds in the CNS. Coupling the knockout of the mdrla and 1b genes with an inducible transgene system that governs PrPc expression, will allow us to measure the clearance of PrPSc as a function of high concentrations of putative therapeutics in the CNS. Besides facilitating testing of the efficacy of novel compounds, these new Tg mouse models will also aid in validating our in vitro screening targets. So as to expand the number of relevant HTS assays useful in anti-prion drug discovery, we also propose to undertake a shRNA screen to identify non-PrP genes that are involved with prion expression, replication and clearance. This study may shed light on the biology of prion disease, and importantly, lead to the development of novel HTS assays to identify selective ligands for non-PrP targets that reduce or inhibit the progression of prion disease. The development of a substantial array of HTS assays may eventually lead to an armamentarium of therapeutic compounds, which when used in concert halt the propagation of prions and hence, the progression of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG031220-05
Application #
8220809
Study Section
Special Emphasis Panel (ZRG1-BST-Q (52))
Program Officer
Mackiewicz, Miroslaw
Project Start
2008-02-15
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$578,495
Indirect Cost
$204,065
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Silber, B Michael; Gever, Joel R; Rao, Satish et al. (2014) Novel compounds lowering the cellular isoform of the human prion protein in cultured human cells. Bioorg Med Chem 22:1960-72
Stöhr, Jan; Condello, Carlo; Watts, Joel C et al. (2014) Distinct synthetic A? prion strains producing different amyloid deposits in bigenic mice. Proc Natl Acad Sci U S A 111:10329-34
Watts, Joel C; Giles, Kurt; Patel, Smita et al. (2014) Evidence that bank vole PrP is a universal acceptor for prions. PLoS Pathog 10:e1003990
Watts, Joel C; Prusiner, Stanley B (2014) Mouse models for studying the formation and propagation of prions. J Biol Chem 289:19841-9
Watts, Joel C; Condello, Carlo; Stöhr, Jan et al. (2014) Serial propagation of distinct strains of A? prions from Alzheimer's disease patients. Proc Natl Acad Sci U S A 111:10323-8
Li, Zhe; Gever, Joel; Rao, Satish et al. (2013) Discovery and Preliminary SAR of Arylpiperazines as Novel, Brainpenetrant Antiprion Compounds. ACS Med Chem Lett 4:397-401
Berry, David B; Lu, Duo; Geva, Michal et al. (2013) Drug resistance confounding prion therapeutics. Proc Natl Acad Sci U S A 110:E4160-9
Silber, B Michael; Rao, Satish; Fife, Kimberly L et al. (2013) Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice. Pharm Res 30:932-50
Dehdashti, Seameen J; Zheng, Wei; Gever, Joel R et al. (2013) A high-throughput screening assay for determining cellular levels of total tau protein. Curr Alzheimer Res 10:679-87
Li, Zhe; Rao, Satish; Gever, Joel R et al. (2013) Optimization of Arylamides as Novel, Potent and Brain-penetrant Antiprion Lead Compounds. ACS Med Chem Lett 4:647-650

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