 |
Jiri G. Safar, M.D.Associate ProfessorMailing Address: fax: (216)368-4090 email: Jiri.Safar@Case.edu |
Biography
Jiri G. Safar is Co-Director of the National Prion Disease Pathology Surveillance Center (NPDPSC)
and Associate Professor in the Department of Pathology at Case Western Reserve University. An
internationally renowned neuroscientist and biochemist with over 20 years in the prion field, he is a
leader in research on prion diseases, i.e. neurodegenerative disorders such as Creutzfeldt-Jakob
Disease (CJD), caused by protein misfolding.
Dr. Safar earned his MD from the School of Medicine at Charles University, Prague, Czech Republic. Following his board certification in neurology, PhD training in biochemistry, and Research Fellowship at the National Institute of Neurological Disorders and Stroke (NINDS), of the National Institutes of Health (NIH), Bethesda, Maryland, he served as Senior Scientist (1989-1996) in the Laboratory of Central Nervous System Studies at NINDS. Here he demonstrated that the difference between normal and pathogenic prion protein lies in conformational transition, and he introduced the novel concept of the folding intermediate as a crucial stage in prion formation. For this groundbreaking research, he received the NIH Award of Merit.
After serving at the NINDS, Dr. Safar joined the Institute for Neurodegenerative Diseases at the University of California at San Francisco (UCSF), and became Associate Professor in the Department of Neurology. During his 12 years at UCSF he extended the reach of his investigations by discovering a new prion protein isoform, by deciphering conformational mechanisms of prion strains, and by leading a research team that developed a preclinical blood test for the detection of human prions. This test is crucial for improving the safety of blood supply, for organ transplant programs, and for effective therapy for diseases caused by protein misfolding.
Dr. Safar holds 27 patents, including one for a method to detect misfolded proteins and another for a device that removes prions from blood, plasma and other liquids. His international stature is firmly established: He served on the British Spongiform Encephalopathy Advisory Committee (SEAC) from 1999 to 2003, he is a member of the European Union’s Prion Expert Group (Weybridge, Surrey, UK); and a member of the World Health Organization’s Advisory Board for Prion Diseases. He is the author of over 160 scientific papers or book chapters, encompassing a broad range of research in molecular biology, immunology, and biochemistry of human and animal prion diseases. His 1998 Nature Medicine paper is the most quoted original work published on prions in the past ten years (Institute for Scientific Information, 1998-2008).
Research
Safar Laboratory at the Department of Pathology is a part of the National Prion Disease Pathology
Surveillance Center (NPDPSC,
http://www.cjdsurveillance.com/) and focuses on research in three crucial areas of prion diseases in
which knowledge remains inadequate:
The Molecular Basis of Prion Disease
Through methods such as immunochemistry, spectroscopy, and atomic force microscopy, the laboratory
is attempting to deepen knowledge of the structure of the prion protein in both its normal and
pathogenic forms, so that efficient diagnostic tools and therapies can be developed.
Diagnostics
Since a definitive diagnosis of CJD is usually established only when the disease is far advanced, it
is essential that a preclinical test be developed which can diagnose the condition at the earliest
possible time so that drug therapy can be instituted for CJD as well as other prion diseases. The
laboratory is working on such a test.
Surveillance for human prion diseases
With the support of the Centers for Disease Control and Prevention (CDC) and of the National Institutes
of Health (NIH), the laboratory is developing innovative conformational methods to understand the impact
of the pathogenic prion protein upon the phenotype and the transmissibility, and to enhance
differentiation and classification of human prions. These techniques are crucial in the surveillance
of emerging prions and of prions that may cross the species barrier from nonhuman reservoirs like scrapie
in sheep, or chronic wasting diseases (CWD) in deer.
Publications
Selected Peer Reviewed Journal Articles and Book Chapters
Wille H, Shanmugam M, Murugesu M, Ollesch J, Stubbs G, Long JR, Safar JG, Prusiner SB. Surface charge
of polyoxometalates modulates polymerization of the scrapie prion protein. Proc Natl Acad Sci U S A. 2009
Mar 10;106(10):3740-5.
Safar, J.G., Lessard, P., Tamgüney, G., Freyman, Y., Deering, C., Letessier, F., Dearmond, S.J., Prusiner, S.B. (2008) Transmission and detection of prions in feces. J Infect Dis. 198(1):81-9.
King, D.J., Safar, J.G., Legname, G., Prusiner, S.B. (2007) Thioaptamer Interactions with Prion Proteins: Sequence-specific and Non-specific Binding Sites. J Mol Biol. 369, 1001–1014.
Phuan, P.W., Zorn, J.A., Safar, J., Giles, K., Prusiner, S.B., Cohen, F.E., May, B.C. (2007) Discriminating between cellular and misfolded prion protein by using affinity to 9-aminoacridine compounds. J Gen Virol. 2007 88(4):1392-401.
Peretz, D. Supattapone, S., Giles, K., Vergara. J., Safar, J.G., Glidden, D.V., McCulloch, C., Nguyen, H-O.B., Scott, M., DeArmond, S.J., Prusiner, S.B. (2006) Inactivation of prions by acidic sodium dodecyl sulfate. J. Virol., 80(1):322-31.
Tamguney, G., Giles, K., Bouzamondo-Bernstein, E., Bosque, P.J., Miller, M.W., Safar, J., DeArmond, S.J., Prusiner, S.B. (2006) Transmission of elk and deer prions to transgenic mice. J Virol. 80(18):9104- 14.
Safar, J.G., Wille, H., Geschwind, M.D., Deering, C., Latawiec, D., Serban, A., King, D.J., Legname, G., Weisgraber, K.H., Mahley, R.W., Miller. B.L., Dearmond, S.J., Prusiner, S.B. (2006) Human prions and plasma lipoproteins. PNAS U S A. 103(30):11312-7.
Lee, I.S., Long, J.R., Prusiner, S.B., Safar, J.G. (2005) Selective precipitation of prions by polyoxometalate complexes. J. Am. Chem. Soc., 127(40):13802-3.
Safar, J.G., DeArmond, S., Kociuba, K., Deering, D, Didorenko, S., Bouzamondo-Bernstein, E., Prusiner, S.B., Tremblay, P. (2005) Prion clearance in bigenic mice. J. Gen. Virol., 86(Pt 10):2913-23.
Safar, J.G., Kellings, K., Serban, A., Groth, G., Cleaver, J., Prusiner, S.B., Riesner, D. (2005) Search for a prion-specific nucleic acid. J. Virol., 79(16):10796-806.
Safar, J.G., Geschwind, M.D., Deering, C., Didorenko, S., Sattavat, M., Sanchez, H., Serban, A., Vey, M., Baron, H., Giles, K., Miller, B.L., Dearmond, S.J., Prusiner, S.B. (2005) Diagnosis of human prion disease. Proc. Natl. Acad. Sci. U S A. Mar 1;102(9):3501-6
Bouzamondo-Bernstein, E., Hopkins, S.D., Spilman, P., Uyehara-Lock, J., Deering, C., Safar, J.G., Prusiner, S.B., Ralston, H.J. 3rd, DeArmond, S.J. (2004) The neurodegeneration sequence in prion diseases: evidence from functional, morphological and ultrastructural studies of the GABAergic system. J. Neuropathol. Exp. Neurol.. Aug; 63(8):882-99.
Goldman, J.S., Miller, B.L., Safar, J., de Tourreil, S., Martindale, J.L., Prusiner, S.B., Geschwind, M.D. (2004) When sporadic disease is not sporadic: the potential for genetic etiology. Arch. Neurol. 61(2):213-6.
Tremblay, P., Ball, H.L., Kaneko K., Groth, D., Hegde, R.S., Cohen, F.E., DeArmond, S., Prusiner, S.B., Safar, J.G. (2004) Mutant PrPSc conformers induced by a synthetic peptide and various prion strains. J. Virol. 78(4):2088-99.
Leclerc, E., Peretz, D., Ball, H., Solforosi, L., Legname, G., Safar, J., Serban, H., Prusiner, S.B., Burton, D.R., Williamson, R.A. (2003) Conformation of PrPC on the cell surface as probed by antibody. J. Mol. Biol. 326:475-83.
Perrier, V., Kaneko, K., Safar, J., Vergara, J., Tremblay, P., DeArmond, S.J., Cohen, F.E., Prusiner, S.B., Wallace, A.C. (2002) Dominant-negative inhibition of prion replication in transgenic mice. Proc. Natl. Acad. Sci. U S A. 20:13079-84.
Safar, J.G., Scott, M., Monaghan, J., Deering, C., Didorenko, S., Vergara, J., Ball, H., Legname, G., Leclerc, E., Solforosi, L., Serban, H., Groth, D., Burton, D.R., Prusiner, S.B., Williamson, R.A. (2002) Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice. Nature Biotech. 11:1147-50.
Supattapone, S., Wille, H., Uyechi, L., Safar, J., Tremblay, P., Szoka, F., Cohen, F., Prusiner, S.B., Scott, M.R. (2001) Branched polyamines cure prion-infected neuroblastoma cells. J. Virol. 75: 3453-3461.
Perrier, V., Wallace, A. C., Kaneko, K., Safar, J., Prusiner, S. B., Cohen, F. E. (2000) Mimicking dominant negative inhibition of prion replication through structure-based drug design. Proc. Natl. Acad. Sci. USA 97: 6073-6078.
Kaneko, K., Ball, H. L., Wille, H., Zhang, H., Groth, D., Torchia, M., Tremblay, P., Safar, J., Prusiner, S. B., DeArmond, S. J., Baldwin, M. A., Cohen, F. E. (2000) A synthetic peptide initiates Gerstmann-Straussler-Scheinker (GSS) disease in transgenic mice. J. Mol. Biol. 295: 997-1007.
Supattapone, S., Bosque, P., Muramoto, T., Wille, H., Aagaard, C., Peretz, D., Nguyen, H., Heinrich, C., Torchia, M., Safar, J., Cohen, F.E., DeArmond, S.J., Prusiner, S.B. (1999) Prion protein of 106 residues creates an artificial transmission barrier for prion replication in transgenic mice. Cell 96: 869-878.
Safar, J., Wille, H., Itri, V., Groth, D., Serban, H., Torchia, M., Cohen F.E., Prusiner, S.B. (1998) Eight prion strains have PrPSc molecules with different conformations. Nature Medicine 4: 1157- 1165.
Stockel, J., Safar, J., Wallace, A.C., Cohen, F.E., Prusiner, S.B. (1998) Prion protein selectively binds copper (II) ions. Biochemistry 37: 7185-7193.
Scott, M.R., Safar, J., Telling, G., Nguyen, O., Groth, D., Torchia, M., Koehler, R., Tremblay, P., Walther, D., Cohen, F.E., DeArmond, S.J., Prusiner, S.B. (1997) Identification of a prion protein epitope modulating transmission of bovine spongiform encephalopathy prions to transgenic mice. Proc. Natl. Acad. Sci. USA 94: 14279-14284.
Pergami, P., Jaffe, H., Safar, J. (1996) Semipreparative chromatographic method to purify the normal cellular isoform of the prion protein in non-denatured form. Anal. Biochem 236: 63-73.
Brown, P., Kenney, K., Little, B., Ironside, J., Will, R., Cervenakova, L., Bjork, R.J., San Martin, R.A., Safar, J., Roos, R., Haltia, M., Gibbs, C.J., Jr., Gajdusek, D.C. (1995) Intracerebral distribution of infectious amyloid protein in spongiform encephalopathy. Ann. Neurol. 38: 245-253.
DiMartino, A., Safar, J., Gibbs Jr., C.J. (1994) The consistent use of organic solvents for purification of phospholipids from brain tissue effectively removes scrapie infectivity. Biologicals, 22: 221-225.
Safar, J., Roller, P.P., Gajdusek, D.C., Gibbs Jr., C.J. (1994) Scrapie amyloid (prion) protein has the conformational characteristics of an aggregated molten globule folding intermediate. Biochemistry, 33: 8375-8383.
Jordan, K., Woodward, R.A., Shifaro, Y., Black, J., Safar, J. (1994) Intra-blood brain barrier IgG synthesis rate and blood brain barrier function in normal rhesus monkeys. Primates, 35: 473-487.
Safar, J., Roller, P.P., Gajdusek, D.C., Gibbs Jr., C.J. (1993) The thermal stability and conformational transitions of scrapie amyloid (prion) protein correlate with infectivity. Protein Sci., 2: 2206-2216.
Guiroy, D.C., Mellini, M., Miyzaki, M., Hilbich, C., Safar, J., Garruto, R.M., Yanagihara, R., Beyreuther, K., Gajdusek, D.C. (1993) Neurofibrillary tangles of Guamanian amyotrophic lateral sclerosis, parkinsonism-dementia and neurologically normal Guamanians contain a 4- to 4.5-kilodalton protein which is immunoreactive to anti-amyloid b/A4-protein antibodies. Acta Neuropathol., 86: 265-274.
Safar, J., Roller, P.P., Gajdusek, D.C., Gibbs Jr., C.J. (1993) Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein. J. Biol. Chem., 268: 20276- 20284.
DiMartino, A., Safar, J., Ceroni, M., Gibbs Jr., C.J. (1993) Inactivation of the scrapie agent in a scaled-down procedure for the purification of gangliosides from brain tissue. In: Transmissible Spongiform Encephalopathies - Impact on Animal and Human Health, Dev. Biol. Stand. 80: 187-194.
Safar, J., Roller, P.P., Ruben, G.C., Gajdusek, D.C., Gibbs Jr., C.J. (1993) Secondary structure of proteins associated in thin films. Biopolymers, 33: 1461-1476.
DiMartino, A., Safar, J., Callegaro, L., Gibbs Jr., C.J. (1992) Ganglioside composition changes in spongiform encephalopathies: Analysis of 263K scrapie-infected hamster brains. Neurochem. Res., 18 (8): 907-913.
DiMartino, A., Safar, J., Ceroni, M., Gibbs Jr., C.J. (1992) Purification of non-infectious ganglioside preparations from scrapie-infected brain tissue. Arch. Virol., 124 (1-2): 111-121.
Safar, J., Gibbs Jr., C.J., Gajdusek, D.C. (1991) Biochemical studies of the precursor of scrapie amyloid. Brain Res. Rev. 16: 103-105.
Safar, J., Ceroni, M., Gajdusek, D.C., Gibbs, C.J., Jr. (1991) Differences in membrane-interaction of scrapie amyloid precursor proteins in normal and scrapie or Creutzfeldt-Jakob disease infected brains. J. Inf. Dis. 163: 488-494.
Safar, J., Wang, W., Paodett, M.P., Ceroni, M., Piccardo, P., Zopf, D., Gibbs, C.J., Jr., Gajdusek, D.C. (1990) Molecular mass, biochemical composition and physicochemical behavior of the infectious form of the scrapie precursor protein monomer. PNAS USA 87: 6373-6377.
Gibbs , C.J., Jr. Safar, J., Ceroni, M., DiMartino, A., Clark, W.W., Hourrigan, J.L. (1990) Experimental transmission of scrapie to bovine species. Lancet 335: 1275.
Wang, W., Safar, J. Zopf, D. (1990) Analysis of inositol by high performance liquid chromatography. Anal. Biochem. 188: 432-435.
Safar, J., Ceroni, M., Piccardo, P., Gajdusek, D.C., Gibbs, C.J., Jr. (1990b) Scrapie associated precursor proteins: Antigenic relationship between species and immunocytochemical localization in normal, scrapie and CJD brains. Neurology 40: 513-517.
Safar, J., Ceroni, M., Piccardo, P., Liberski, P.P., Miyazaki, M., Gajdusek, D.C., Gibbs, C.J., Jr. (1990a) Subcellular distribution and physicochemical properties of scrapie-associated precursor protein and relationship with scrapie agent. Neurology 40: 503-508.
Piccardo, P., Safar, J., Ceroni, M., Gajdusek, D.C., Gibbs, C.J.,.Jr. (1990) Immunohistochemical localization of prion protein in spongiform encephalopathies and normal brain tissue. Neurology 40: 518-522.
Ceroni, M., Piccardo, P., Safar, J., Gajdusek, D.C. Gibbs, C.J,.Jr. (1990) Scrapie infectivity and prion protein are distributed in the same pH range in agarose isoelectric focusing. Neurology 40: 508- 513.
Book Chapters
Baron, H., Safar, J., Groth, D., DeArmond, S.J., Prusiner, S.B. (2004) Biosafety issues in
prion diseases. In: Prion Biology and Diseases, ed. S.B. Prusiner, Second Edition, Cold Spring
Harbor Laboratory Press, Cold Spring Harbor, 921-960.
Prusiner, S.B., Legname, G., DeArmond, S.J. Cohen, F.E., Safar, J., Riesner, D., Kaneko, K. (2004) Some strategies and methods for the study of prions. In: Prion Biology and Diseases, ed. S.B. Prusiner, Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 857-920.
Prusiner, S.B., Safar, J., DeArmond, S.J. (2004) Bioassays of prions. In: Prion Biology and Diseases, ed. S.B. Prusiner, Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 143- 186.
Safar, J., Cohen F.E., Prusiner, S.B. (2001) Conformation of the Prion Protein Encodes Quantitative Traits of Prion Strains. In: Prionen und Prionkrankheiten, ed. Beat Horlimann, Detlev Riesner and Hans Kretzschmar, W. de Gruyter, Berlin – New York, 1-620.
Baron, H., Safar, J., Groth, D., DeArmond, S.J., Prusiner, S.B. (2001) Prions. In: Disinfection, Sterilization, and Preservation, ed. Seymour S. Block, Lippincott and Wilkins, Philadelphia, 659-675.