DEGENERATIVE AND DEMENTING DISEASES OF AGING

Summary

Principal Investigator: Stanley B Prusiner
Abstract: In this application comprising four scientific projects and four-cores, we propose to continue our studies focused on neurodegeneration caused by human prion diseases, the most common of which is sporadic (s) CJD. Prions seem to be composed solely of PrPSc molecules, which are derived from a precursor PrPc by a poorly understood process. The studies described here are aimed at defining the structure of PrPSc, characterizing the interactions of small molecules with both PrPc and PrPSc and dissecting the molecular events governing the propagation of different human prion strains. In Project 1, we propose to study the interactions of polyoxometalates (POMs) with PrPSc. The POM phosphotungstate anion [PW12O40] (PTA) binds specifically to PrPSc, but not to PrP. POMs are a large class of inorganic metal oxide clusters with rigid polyhedral structures displaying substantial variations in size, shape, and charge density. In Project 2, we propose to carry out fiber diffraction studies of the 55-residue MoPrP(89-143,P101L) peptide that causes inherited prion disease, a 20 mer wt PrP(106-126) peptide known to form amyloid fibrils as well as purified truncated (PrP 27-30) and full-length PrPSc, both of which are infectious in wild-type animals. In Project 3, we propose to study the prions causing sCJD. These studies are possible because our most sensitive Tg mouse line expressing chimeric human/mouse PrP succumbs to disease in ~80 days after inoculation with sCJD prions. Relatively rapid bioassays of human prions in these Tg mice make it practical to measure the titers of prions throughout brain as well as in peripheral organs and body fluids collected from dead sCJD patients. We also propose to develop guinea pig models of sCJD and variant (v) CJD. In Project 4, we propose to discover new ligands that bind to and stabilize human PrPc. We also plan to determine whether such ligands inhibit the conversion of HuPrPc into HuPrPSc. Using a virtual screening approach, large libraries of organic molecules will be docked against the known structure of HuPrPc. High-scoring compounds will be tested for binding biophysically, controlling for non-specific inhibition to which anti-amyloid inhibitors are prone. The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases.
Funding Period: 1997-04-01 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc Fungal prion HET-s as a model for structural complexity and self-propagation in prions
    William Wan
    Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, TN 37235
    Proc Natl Acad Sci U S A 111:5201-6. 2014
  2. pmc Purified and synthetic Alzheimer's amyloid beta (Aβ) prions
    Jan Stöhr
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 109:11025-30. 2012
  3. pmc Identifying mechanism-of-action targets for drugs and probes
    Elisabet Gregori-Puigjané
    Department of Pharmaceutical Chemistry, University of California, 1700 Fourth Street, San Francisco, CA 94143 2550, USA
    Proc Natl Acad Sci U S A 109:11178-83. 2012
  4. pmc Degradation of fungal prion HET-s(218-289) induces formation of a generic amyloid fold
    William Wan
    Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA
    Biophys J 102:2339-44. 2012
  5. pmc Colloidal aggregation affects the efficacy of anticancer drugs in cell culture
    Shawn C Owen
    Donnelly Centre, Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, Department of Chemistry, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada
    ACS Chem Biol 7:1429-35. 2012
  6. pmc Salivary prions in sheep and deer
    GULTEKIN TAMGUNEY
    Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, CA, USA
    Prion 6:52-61. 2012
  7. pmc Compartment modeling for mammalian protein turnover studies by stable isotope metabolic labeling
    Shenheng Guan
    Department of Pharmaceutical Chemistry and Mass Spectrometry Facility, University of California, San Francisco, California 94158 2517, USA
    Anal Chem 84:4014-21. 2012
  8. pmc Identification of I137M and other mutations that modulate incubation periods for two human prion strains
    Kurt Giles
    Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA
    J Virol 86:6033-41. 2012
  9. pmc Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein
    Joel C Watts
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 109:3498-503. 2012
  10. pmc Chemical informatics and target identification in a zebrafish phenotypic screen
    Christian Laggner
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA
    Nat Chem Biol 8:144-6. 2012

Detail Information

Publications78

  1. pmc Fungal prion HET-s as a model for structural complexity and self-propagation in prions
    William Wan
    Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, TN 37235
    Proc Natl Acad Sci U S A 111:5201-6. 2014
    ..Propagation of prion structure seems to require an obligatory level of complexity that may not be reproducible in short peptide models. ..
  2. pmc Purified and synthetic Alzheimer's amyloid beta (Aβ) prions
    Jan Stöhr
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 109:11025-30. 2012
    ..Our results create an experimental paradigm that should lead to identification of self-propagating Aβ conformations, which could represent novel targets for interrupting the spread of Aβ deposition in AD patients...
  3. pmc Identifying mechanism-of-action targets for drugs and probes
    Elisabet Gregori-Puigjané
    Department of Pharmaceutical Chemistry, University of California, 1700 Fourth Street, San Francisco, CA 94143 2550, USA
    Proc Natl Acad Sci U S A 109:11178-83. 2012
    ..A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest...
  4. pmc Degradation of fungal prion HET-s(218-289) induces formation of a generic amyloid fold
    William Wan
    Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA
    Biophys J 102:2339-44. 2012
    ..Taken together, these observations suggest that the functional or pathological forms of amyloid proteins are more complex than the simple generic stacked-sheet amyloids commonly formed by short peptides...
  5. pmc Colloidal aggregation affects the efficacy of anticancer drugs in cell culture
    Shawn C Owen
    Donnelly Centre, Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, Department of Chemistry, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada
    ACS Chem Biol 7:1429-35. 2012
    ....
  6. pmc Salivary prions in sheep and deer
    GULTEKIN TAMGUNEY
    Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, CA, USA
    Prion 6:52-61. 2012
    ..Salivary prions shed into the environment provide an additional mechanism for horizontal prion transmission...
  7. pmc Compartment modeling for mammalian protein turnover studies by stable isotope metabolic labeling
    Shenheng Guan
    Department of Pharmaceutical Chemistry and Mass Spectrometry Facility, University of California, San Francisco, California 94158 2517, USA
    Anal Chem 84:4014-21. 2012
    ....
  8. pmc Identification of I137M and other mutations that modulate incubation periods for two human prion strains
    Kurt Giles
    Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA
    J Virol 86:6033-41. 2012
    ..Our studies contend that strain-specified replication of prions is modulated by PrP sequence-specific interactions between the prion precursor PrP(C) and the infectious product PrP(Sc)...
  9. pmc Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein
    Joel C Watts
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 109:3498-503. 2012
    ..Thus, Tg(BVPrP) mice may be useful for studying the spontaneous formation of prions, and thus may provide insight into the etiology of sporadic CJD...
  10. pmc Chemical informatics and target identification in a zebrafish phenotypic screen
    Christian Laggner
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA
    Nat Chem Biol 8:144-6. 2012
    ..The roles of two of these targets were tested in the original zebrafish phenotype. Prediction of targets from chemotype is rapid and may be generally applicable...
  11. pmc Protease-resistant prions selectively decrease Shadoo protein
    Joel C Watts
    Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, United States of America
    PLoS Pathog 7:e1002382. 2011
    ..Additional studies using this paradigm may provide insight into the cellular pathways and systems subverted by PrP(Sc) during prion disease...
  12. pmc Spontaneous generation of anchorless prions in transgenic mice
    Jan Stöhr
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 108:21223-8. 2011
    ..Remarkably, disease from ill Tg(PrP,ΔGPI) mice transmitted to mice expressing wild-type PrP(C), indicating the spontaneous generation of prions...
  13. pmc Self-assembling small molecules form nanofibrils that bind procaspase-3 to promote activation
    Julie A Zorn
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA
    J Am Chem Soc 133:19630-3. 2011
    ..These studies demonstrate a novel approach for proenzyme activation through binding to fibrils, which may mimic how procaspases are naturally processed on protein scaffolds...
  14. pmc De novo generation of prion strains
    David W Colby
    Department of Chemical Engineering, University of Delaware, Newark, Delaware 19716, USA
    Nat Rev Microbiol 9:771-7. 2011
    ..These advances promise unprecedented insight into the structure of prions and the mechanisms by which they originate and propagate...
  15. pmc Conformational transformation and selection of synthetic prion strains
    Sina Ghaemmaghami
    Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA 94143, USA
    J Mol Biol 413:527-42. 2011
    ..Rare conformational conversion, followed by competitive selection among the resulting pool of conformers, provides a mechanism for the adaptation of the prion population to its host environment...
  16. pmc Conserved properties of human and bovine prion strains on transmission to guinea pigs
    Jiri G Safar
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143 0518, USA
    Lab Invest 91:1326-36. 2011
    ..Such strain-specific properties were maintained in Gps as well as mice expressing a chimeric human/mouse transgene. Gps may prove particularly useful in further studies of novel human prions such as those causing vCJD...
  17. pmc A survey of antiprion compounds reveals the prevalence of non-PrP molecular targets
    Guillaume Poncet-Montange
    Department of Neurology, University of California, San Francisco, California 94143, USA
    J Biol Chem 286:27718-28. 2011
    ..Our findings indicate that in comparison to PrP conformers themselves, proteins that play auxiliary roles in prion propagation may be more effective targets for future drug discovery efforts...
  18. pmc Human prion strain selection in transgenic mice
    Kurt Giles
    Institute for Neurodegenerative Diseases, University of California at San Francisco, 94143 0518, USA
    Ann Neurol 68:151-61. 2010
    ..Increasing the sequence similarity of the chimeric PrP to mouse PrP, by reverting human residues to mouse, resulted in a Tg line, denoted Tg22372, which was susceptible to sporadic (s) CJD prions in approximately 110 days...
  19. pmc Large-scale prediction and testing of drug activity on side-effect targets
    Eugen Lounkine
    Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA
    Nature 486:361-7. 2012
    ..The clinical relevance of this inhibition was borne out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery...
  20. pmc Fiber diffraction data indicate a hollow core for the Alzheimer's aβ 3-fold symmetric fibril
    Michele McDonald
    Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235 1634, USA
    J Mol Biol 423:454-61. 2012
    ..Refinement of a hollow-core model against ssNMR data led to a revised ssNMR model, similar to the fiber diffraction model...
  21. pmc Novel epitopes identified by anti-PrP monoclonal antibodies produced following immunization of Prnp0/0 Balb/cJ mice with purified scrapie prions
    Larry H Stanker
    USDA Agriculture Research Service, Foodborne Contaminants Research Unit, Albany, California 94710, USA
    Hybridoma (Larchmt) 31:314-24. 2012
    ..Our novel anti-PrP MAbs with defined PrP epitopes may be useful in deciphering the conformational conversion of PrP(C) into PrP(Sc)...
  22. pmc Evidence that bank vole PrP is a universal acceptor for prions
    Joel C Watts
    Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, United States of America Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America
    PLoS Pathog 10:e1003990. 2014
    ..Our results demonstrate that expression of BVPrP is sufficient to engender enhanced susceptibility to a diverse range of prion isolates, suggesting that BVPrP may be a universal acceptor for prions...
  23. pmc Fiber diffraction of the prion-forming domain HET-s(218-289) shows dehydration-induced deformation of a complex amyloid structure
    William Wan
    Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37235 1634, United States
    Biochemistry 53:2366-70. 2014
    ..The dehydration-related structural deformation of HET-s(218-289) indicates that water can play a significant role in complex amyloid structures, even when no obvious water-accessible cavities are present. ..
  24. pmc Novel compounds lowering the cellular isoform of the human prion protein in cultured human cells
    B Michael Silber
    Institute for Neurodegenerative Diseases, University of California, San Francisco, United States Department of Neurology, University of California, San Francisco, United States Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, United States
    Bioorg Med Chem 22:1960-72. 2014
    ....
  25. pmc Is supramolecular filament chirality the underlying cause of major morphology differences in amyloid fibrils?
    Dmitry Kurouski
    Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany, New York 12222, United States
    J Am Chem Soc 136:2302-12. 2014
    ..Because fibril morphology is linked to cell toxicity, the chirality of amyloid aggregates should be explored in the widely used in vitro models of amyloid-associated diseases. ..
  26. pmc Biology and genetics of prions causing neurodegeneration
    Stanley B Prusiner
    Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, California 94143 email
    Annu Rev Genet 47:601-23. 2013
    ....
  27. pmc Transmission of multiple system atrophy prions to transgenic mice
    Joel C Watts
    Institute for Neurodegenerative Diseases, and Departments of Neurology and Pathology, University of California, San Francisco, CA 94143
    Proc Natl Acad Sci U S A 110:19555-60. 2013
    ..The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago. ..
  28. pmc Antiprion compounds that reduce PrP(Sc) levels in dividing and stationary-phase cells
    B Michael Silber
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, United States Department of Neurology, University of California, San Francisco, CA 94143, United States Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, United States
    Bioorg Med Chem 21:7999-8012. 2013
    ..5 and 1.6 μM, respectively. Unexpectedly, the number of hits in stationary-phase cells was ~10% of that in dividing cells. The explanation for this difference remains to be determined...
  29. pmc Drug resistance confounding prion therapeutics
    David B Berry
    Institute for Neurodegenerative Diseases, Departments of Neurology and Pathology, and Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143
    Proc Natl Acad Sci U S A 110:E4160-9. 2013
    ..These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration...
  30. pmc Heterogeneous seeding of a prion structure by a generic amyloid form of the fungal prion-forming domain HET-s(218-289)
    William Wan
    From the Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37235 1634
    J Biol Chem 288:29604-12. 2013
    ....
  31. pmc Biaryl amides and hydrazones as therapeutics for prion disease in transgenic mice
    Duo Lu
    Institute for Neurodegenerative Diseases D L, K G, Z L, S R, J R G, M G, M L E, S J D, B M S, S B P, Department of Neurology K G, Z L, S R, J R G, B M S, S B P, Department of Pathology A O, S J D, Department of Pharmaceutical Chemistry E D, C B, A R R, M P J, Department of Bioengineering and Therapeutic Sciences B M S, and Small Molecule Discovery Center C B, A R R, University of California, San Francisco, California
    J Pharmacol Exp Ther 347:325-38. 2013
    ..The BLI system successfully predicted the efficacies in all cases long before extension in survival could be observed. Our studies suggest that this BLI system has good potential to be applied in future antiprion drug efficacy studies. ..
  32. pmc 2-Aminothiazoles with improved pharmacotherapeutic properties for treatment of prion disease
    Zhe Li
    Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143, USA
    ChemMedChem 8:847-57. 2013
    ....
  33. pmc Plasma membrane invaginations containing clusters of full-length PrPSc are an early form of prion-associated neuropathology in vivo
    Susan F Godsave
    Department of Cell Biology II, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    Neurobiol Aging 34:1621-31. 2013
    ..Only a small proportion of clustered PrP immunogold labeling was found at synapses, indicating that synapses are not targeted specifically in prion disease...
  34. pmc Convergent replication of mouse synthetic prion strains
    Sina Ghaemmaghami
    Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California 94143 0518, USA
    Am J Pathol 182:866-74. 2013
    ..These results indicate that synthetic prions can assume multiple intermediate conformations before converging into one conformation optimized for in vivo propagation...
  35. pmc Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice
    B Michael Silber
    Institute for Neurodegenerative Diseases, University of California, San Francisco, California, USA
    Pharm Res 30:932-50. 2013
    ..To discover drugs lowering PrP(Sc) in prion-infected cultured neuronal cells that achieve high concentrations in brain to test in mouse models of prion disease and then treat people with these fatal diseases...
  36. pmc Chimeric elk/mouse prion proteins in transgenic mice
    GULTEKIN TAMGUNEY
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA
    J Gen Virol 94:443-52. 2013
    ..Our findings highlight the role of C-terminal residues in PrP that control the susceptibility and replication of prions...
  37. pmc Generation of antisera to purified prions in lipid rafts
    Robert Hnasko
    USDA Agricultural Research Service, Foodborne Contaminants Research Unit, Albany, CA, USA
    Prion 4:94-104. 2010
    ..In contrast, the PrP(Sc) inoculum was non-immunogenic in wt mice and antisera showed no reactivity with PrP or any other protein...
  38. pmc Conformation-dependent high-affinity monoclonal antibodies to prion proteins
    Larry H Stanker
    Foodborne Contaminants Research Unit, U S Department of Agriculture Agricultural Research Service, Albany, CA 94710, USA
    J Immunol 185:729-37. 2010
    ..These new conformation-dependent mAbs were found to be particularly useful in histoblotting studies, in which the low backgrounds after treatment with 2-ME created unusually high signal-to-noise ratios...
  39. pmc Prion detection by an amyloid seeding assay
    David W Colby
    Institute for Neurodegenerative Diseases corrected, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 104:20914-9. 2007
    ..Our studies show that the ASA provides an alternative methodology for detecting both sPrP(Sc) and protease-resistant PrP(Sc) that does not rely on protease digestion or immunodetection...
  40. pmc Cell division modulates prion accumulation in cultured cells
    Sina Ghaemmaghami
    Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 104:17971-6. 2007
    ..Our results suggest that the apparent effectiveness of antiprion compounds in culture may be strongly influenced by the growth phase of the target cells...
  41. pmc Electron crystallography of the scrapie prion protein complexed with heavy metals
    Holger Wille
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA Department of Neurology, University of California, San Francisco, CA 94143, USA
    Arch Biochem Biophys 467:239-48. 2007
    ..Differential staining also confirmed the location of the internal deletion of PrP(Sc)106 at or near these densities...
  42. ncbi Influence of water, fat, and glycerol on the mechanism of thermal prion inactivation
    Henrik Müller
    Institut für Physikalische Biologie, Heinrich Heine Universitat Dusseldorf, D 40225 Dusseldorf, Germany
    J Biol Chem 282:35855-67. 2007
    ..These findings suggest that prion infectivity depends on beta-sheet-rich fibrillar structure and that inactivation proceeds in a stepwise manner, which explains the tailing effect frequently observed during inactivation...
  43. ncbi Thioaptamer interactions with prion proteins: sequence-specific and non-specific binding sites
    David J King
    Institute for Neurodegenerative Diseases, University of California San Francisco, CA 94143 0518, USA
    J Mol Biol 369:1001-14. 2007
    ..In contrast, the high-affinity binding of thioaptamer 97 to PrP depends on (1) backbone modifications, (2) oligonucleotide sequence, and (3) PrP sequence...
  44. ncbi Discriminating between cellular and misfolded prion protein by using affinity to 9-aminoacridine compounds
    Puay Wah Phuan
    Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
    J Gen Virol 88:1392-401. 2007
    ....
  45. pmc Developmental expression of PrP in the post-implantation embryo
    Patrick Tremblay
    Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, CA 94143 0518, USA
    Brain Res 1139:60-7. 2007
    ..This pattern of Prnp expression in the nervous system appears to persist throughout the adult life of mammals...
  46. ncbi Specific features of the prion protein transmembrane domain regulate nascent chain orientation
    Carolyn M Ott
    Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA
    J Biol Chem 282:11163-71. 2007
    ..Because position 129 is the location of the disease-associated Met/Val polymorphism, we discuss both how this small change may affect TMD orientation and the larger biological implications of these results...
  47. ncbi Structure-activity relationship study of prion inhibition by 2-aminopyridine-3,5-dicarbonitrile-based compounds: parallel synthesis, bioactivity, and in vitro pharmacokinetics
    Barnaby C H May
    Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California 94158, USA
    J Med Chem 50:65-73. 2007
    ....
  48. pmc Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes
    Giuseppe Legname
    Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 103:19105-10. 2006
    ..The biophysical explanation for the unprecedented plasticity of PrP(Sc) remains to be determined...
  49. ncbi Discovering DNA encodes heredity and prions are infectious proteins
    Stanley B Prusiner
    Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, California 94143, USA
    Annu Rev Genet 40:25-45. 2006
    ..Finding the unexpected and being asked to demonstrate unequivocally the absence of a possible contaminant represent uncanny parallels between the discoveries that DNA encodes the genotype and that prions are infectious proteins...
  50. pmc Transmission of elk and deer prions to transgenic mice
    GULTEKIN TAMGUNEY
    Institute for Neurodegenerative Diseases, University of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143 0518, USA
    J Virol 80:9104-14. 2006
    ..These findings suggest that CWD prions from elk, mule deer, and white-tailed deer can be readily transmitted among these three cervid species...
  51. ncbi Structure-activity relationship study of 9-aminoacridine compounds in scrapie-infected neuroblastoma cells
    Barnaby C H May
    Institute for Neurodegenerative Diseases, University of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143, USA
    Bioorg Med Chem Lett 16:4913-6. 2006
    ..The efficacy of compounds against PrP(Sc) accumulation was influenced by both substituents of the distal tertiary amine and acridine heterocycle, while cellular cytotoxicity was encoded in the acridine heterocycle substituents...
  52. pmc Human prions and plasma lipoproteins
    Jiri G Safar
    Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 103:11312-7. 2006
    ..Whether detection of PrP(Sc) in VLDL and LDL particles can be adapted into an antemortem diagnostic test for prions in the blood of humans, livestock, and free-ranging cervids remains to be determined...
  53. ncbi Changes in neuropeptide expression in mice infected with prions
    Margarita Diez
    Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
    Neurobiol Aging 28:748-65. 2007
    ..These changes in peptide expression, which mostly occur before appearance of symptoms of disease, may reflect attempts to initiate protective and/or regenerative processes...
  54. pmc Prion infection of mouse neurospheres
    Ranjit K Giri
    McLaughlin Research Institute, Great Falls, MT 59405, USA
    Proc Natl Acad Sci U S A 103:3875-80. 2006
    ..Neurosphere lines from Tg4053 mice provide a sensitive in vitro bioassay for mouse prions; neurosphere lines from other Tg mice overexpressing PrP might be used to assay prions from other species, including humans...
  55. ncbi Developing therapeutics for the diseases of protein misfolding
    Barnaby C H May
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143 2240, USA
    Neurology 66:S118-22. 2006
    ..Due to the underlying molecular basis of this disease class, many of the therapeutic approaches used to target prion misfolding have parallels in other misfolding diseases...
  56. pmc Small-molecule aggregates inhibit amyloid polymerization
    Brian Y Feng
    Department of Pharmaceutical Chemistry and Graduate Group in Chemistry and Chemical Biology, University of California San Francisco, 1700 4th Street, San Francisco, California 94158 2330, USA
    Nat Chem Biol 4:197-9. 2008
    ..They also blocked infection of yeast cells with Sup35 prions, which suggests that colloidal inhibition may be relevant in more biological milieus...
  57. pmc Transmission and detection of prions in feces
    Jiri G Safar
    Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, USA
    J Infect Dis 198:81-9. 2008
    ..Our findings suggest that horizontal transmission of disease among herbivores may occur through the consumption of feces or foodstuff tainted with prions from feces of CWD-infected cervids and scrapie-infected sheep...
  58. pmc Genes contributing to prion pathogenesis
    GULTEKIN TAMGUNEY
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA
    J Gen Virol 89:1777-88. 2008
    ....
  59. pmc Colloid formation by drugs in simulated intestinal fluid
    Allison K Doak
    Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158 2550, USA
    J Med Chem 53:4259-65. 2010
    ..Six formed colloids at concentrations equal to or lower than the concentrations reached in the gut, suggesting that aggregation may have an effect on the absorption and distribution of these drugs, and potentially others, in vivo...
  60. pmc Protease-sensitive synthetic prions
    David W Colby
    Institute for Neurodegenerative Diseases, University of California, San Francisco, California, United States of America
    PLoS Pathog 6:e1000736. 2010
    ..These novel synthetic prions demonstrate that conformational changes in wild-type PrP can produce mouse prions composed exclusively of sPrP(Sc)...
  61. pmc Discovery of 2-aminothiazoles as potent antiprion compounds
    Sina Ghaemmaghami
    Institute for Neurodegenerative Diseases, San Francisco, CA 94143 0518, USA
    J Virol 84:3408-12. 2010
    ..Our results establish 2-aminothiazoles as promising candidates for efficacy studies of animals and validate our drug discovery platform as a viable strategy for the identification of novel lead compounds with antiprion properties...
  62. pmc Continuous quinacrine treatment results in the formation of drug-resistant prions
    Sina Ghaemmaghami
    Institute for Neurodegenerative Diseases, University of California, San Francisco, California, United States of America
    PLoS Pathog 5:e1000673. 2009
    ..Transient accumulation of this drug-resistant prion population provides a possible explanation for the lack of in vivo efficacy of quinacrine and other antiprion drugs...
  63. pmc Chemical induction of misfolded prion protein conformers in cell culture
    Sina Ghaemmaghami
    Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143, USA
    J Biol Chem 285:10415-23. 2010
    ..It remains to be established whether the formation of PrP(A) inhibits the formation of rPrP(Sc) by sequestering PrP(C) in the form of benign, insoluble aggregates...
  64. pmc Design and construction of diverse mammalian prion strains
    David W Colby
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 106:20417-22. 2009
    ....
  65. pmc Natural and synthetic prion structure from X-ray fiber diffraction
    Holger Wille
    Institute for Neurodegenerative Diseases, Departments of Neurology and Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 106:16990-5. 2009
    ....
  66. pmc Evolutionary descent of prion genes from the ZIP family of metal ion transporters
    Gerold Schmitt-Ulms
    Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
    PLoS ONE 4:e7208. 2009
    ..The phylogenetic and spatial connection to ZIP proteins is expected to open new avenues of research to elucidate the biology of the prion protein in health and disease...
  67. pmc Asymptomatic deer excrete infectious prions in faeces
    GULTEKIN TAMGUNEY
    Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143 USA
    Nature 461:529-32. 2009
    ....
  68. pmc Measuring prions by bioluminescence imaging
    GULTEKIN TAMGUNEY
    Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 106:15002-6. 2009
    ..Our studies argue that BLI is likely to be a suitable surrogate for measuring prion infectivity, and might be useful in the study of Tg mouse models for other neurodegenerative illnesses...
  69. ncbi Site-directed mutagenesis demonstrates the plasticity of the beta helix: implications for the structure of the misfolded prion protein
    Jay H Choi
    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
    Structure 17:1014-23. 2009
    ..coli antibiotic sensitivity assay. The results of these experiments suggest that the amyloidogenic PrP fragment may fold into a beta helix in the context of a larger beta-helical structure...
  70. pmc Prion proteins in subpopulations of white blood cells from patients with sporadic Creutzfeldt-Jakob disease
    Ed M Choi
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143 0518, USA
    Lab Invest 89:624-35. 2009
    ..If human WBCs harbor prion infectivity in patients with sCJD, then the levels are likely to be low...
  71. pmc Transmission of scrapie and sheep-passaged bovine spongiform encephalopathy prions to transgenic mice expressing elk prion protein
    GULTEKIN TAMGUNEY
    Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143 0518, USA
    J Gen Virol 90:1035-47. 2009
    ..The susceptibility of 'cervidized' mice to 'ovinized' prions raises the question about why CWD has not been reported in other parts of the world where cervids and scrapie-infected sheep coexist...
  72. pmc Surface charge of polyoxometalates modulates polymerization of the scrapie prion protein
    Holger Wille
    Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 106:3740-5. 2009
    ..The mechanism by which POMs function in competing prion polymerization pathways--one favoring 2D crystals and the other, amyloid fibrils--remains to be established...
  73. pmc Cryo-immunogold electron microscopy for prions: toward identification of a conversion site
    Susan F Godsave
    Section of Tumor Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
    J Neurosci 28:12489-99. 2008
    ..Trypsin digestion of infected hippocampal sections resulted in a reduction in R2 labeling of >85%, which suggests that a high proportion of PrP(Sc) may be oligomeric, protease-sensitive PrP(Sc)...
  74. pmc Resistance of bovine spongiform encephalopathy (BSE) prions to inactivation
    Kurt Giles
    Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA
    PLoS Pathog 4:e1000206. 2008
    ..Our studies contend that any prion inactivation procedures must be validated by bioassay against the prion strain for which they are intended to be used...
  75. pmc A gamma-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains
    Patricia Spilman
    Departments of Pathology and Neurology and Institute for Neurodegenerative Disease, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 105:10595-600. 2008
    ..Whether less toxic GSIs can be used in place of LY411575 to prolong survival remains to be determined...
  76. pmc Inactivation of prions by acidic sodium dodecyl sulfate
    David Peretz
    Institute for Neurodegenerative Diseases, 513 Parnassus Ave, HSE 774, San Francisco, CA 94143 0518, USA
    J Virol 80:322-31. 2006
    ..Our findings form the basis for a noncorrosive system that is suitable for inactivating prions on surgical instruments, as well as on other medical and dental equipment...