Jiri G. Safar, M.D. Associate Professor Mailing Address: 11100 Euclid Ave. Cleveland, OH 44106 phone: (216) 368-4609 fax: (216)368-4090 email: Jiri.Safar@Case.edu

Biography
Jiri G. Safar is Associate Professor in the Departments of Pathology and Neurology at Case Western Reserve University and Co-Director of the National Prion Disease Pathology Surveillance Center (NPDPSC). An internationally renowned neuroscientist and biochemist with over 20 years in the prion field, he is a leader in research on neurodegenerative diseases caused by protein misfolding, such as Creutzfeldt-Jakob Disease (CJD), mad cow disease (BSE), Alzheimer's disease (AD), and Parkinsonism.

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 directed by D.C. Gajdusek (Nobel Prize for Medicine 1976). 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), directed by S.B. Prusiner (Nobel Prize for Medicine 1997), 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 (Prusiner, S.B., Safar, J. (1999) US Patent # 5,891,641) and another for a device that removes prions from blood, plasma and other liquids (Prusiner, S.B., Safar, J. (2001) US Patent # 6,221,614 B1). 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 177 scientific papers and book chapters, encompassing a broad range of research in conformational protein chemistry, molecular biology, immunology, and neurodegeneration in human and animal prion diseases. His 1998 Nature Medicine paper is the most quoted original work published on prions in the past 14 years (Cited 673-times, Institute for Scientific Information, 1998-2012).

Research
Safar Laboratory is situated at the Department of Pathology and has strong long-term collaborations with Department of Physiology and Biophysics, and Department of Neurology. The research focuses on four crucial areas of neurodegenerative diseases caused by protein misfolding 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.

The Role of Small Oligomers of Misfolded Proteins in the Pathogenesis of Neurodegeneration. These projects focus on improving our understanding of the molecular mechanisms governing the phenotypic heterogeneity and progression rates of Alzheimer's diseases (AD) and prion diseases, specifically on different conformers of small oligomers (SOs) of Amyloid beta (Ab) and pathogenic prion protein. This insight is critical for efforts to develop new diagnostic as well as therapeutic strategies targeting the small oligomers of misfolded proteins.

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
Kim, C., Haldiman, T., Cohen, Y., Chen, W., Blevins, J., Sy, M-S., Cohen, M., Safar, J.G. (2011) Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate. PLoS Pathogens 7 (9) e1002242.

Stanker L. H., Serban AV, Cleveland E, Hnasko R, Safar JG, and Prusiner SB. (2010) Conformation-dependent high-affinity monoclonal antibodies to prion proteins. J. Immunol. Jul 1;185(1):729-37.

Cali I, Castellani R, Alshekhlee A, Cohen Y, Blevins J, Yuan J, Langeveld JP, Parchi P, Safar JG, Zou WQ, Gambetti P. (2009) Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt-Jakob disease: its effect on the phenotype and prion-type characteristics. Brain Oct;132(Pt 10):2643-58, Epub 2009 Sep 4.

Wille H, Shanmugam M, Murugesu M, Ollesch J, Stubbs G, Long JR, Safar JG, Prusiner SB. (2009) Surface charge of polyoxometalates modulates polymerization of the scrapie prion protein. Proc Natl Acad Sci U S A. 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.

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., 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

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.

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.

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.

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.

Journal Review Articles
Safar, J.G. (2012) Molecular pathogenesis of sporadic prion diseases in man. Prion 2012 Apr 1;6(2). [Epub ahead of print] PMID: 22421210.