Jiri G. Safar, M.D.

Director, National Prion Disease Pathology Surveillance Center
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 the Director of the National Prion Disease Pathology Surveillance Center, and Associate Professor in the Departments of Pathology and Neurology at Case Western Reserve University. Dr. Safar is internationally recognized leader in research on neurodegenerative diseases caused by protein misfolding, such as Creutzfeldt-Jakob Disease, mad cow disease (BSE), and Alzheimer’s disease. He has more than two decades of research experience in molecular biology, immunology, biochemistry, and conformation of prion proteins. He discovered previously unknown forms of prions, which led to the findings of new prion diseases, better understanding of the conformation of prion proteins, and unraveling molecular mechanisms of prion strains. Dr. Safar invented the Conformation-Dependent Immunoassay (CDI) for detection and differentiation of infectious isoform of the prion protein (PrPSc). The invention was patented internationally, and the CDI test validated for diagnosis of Creutzfeldt-Jakob Disease, and animal diseases (BSE, scrapie) in European Union. It is a completely new approach for detecting prions and other amyloids, including Alzheimer’s disease.

Dr. Safar earned his MD from the School of Medicine at Charles University, Prague, Czech Republic. He is Board Certified in Neurology, and following his postdoctoral training in biochemistry and neuroscience, and Research Fellowship at the National Institute of Neurological Disorders and Stroke (NINDS), he served as a Senior Scientist in the Laboratory of Central Nervous System Studies at the NINDS Bethesda, Maryland, directed by D.C. Gajdusek (Nobel Prize for Medicine 1976). Here he demonstrated that the difference between the 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 National Institutes of Health Award of Merit.

Following his 10-year research appointment at 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 expanded his prion research and discovered a new prion protein isoform, and led a research team that developed a preclinical blood test for the detection of human prions.


Research at Case Western Reserve University

In 2008 Dr. Safar established a new laboratory at the Department of Pathology and developed a strong long-term collaboration with the Department of Physiology and Biophysics, and Department of Neurology. The research team focuses on:

The Molecular Basis of Prion Disease. 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. To improve our understanding of the molecular mechanisms governing the phenotypic heterogeneity and progression rates of Alzheimer’s diseases and prion diseases, specifically on different conformers of small oligomers of Amyloid beta and pathogenic prion protein.

Diagnostics. To develop a preclinical test that can diagnose Creutzfeldt-Jakob Disease as well as other prion diseases at the earliest possible time.

Surveillance of Human Prion Diseases. To develop innovative techniques that 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.


International Service

Prion Expert External Review Panel, Canada; British Spongiform Encephalopathy Advisory Committee, UK; European Union's Prion Expert Group, UK; Medical Research Council, UK; Ministry of Agriculture, Food, and Fisheries, UK; Swiss National Science Foundation, Switzerland; World Health Organization's Advisory Board for Prion Diseases, Switzerland.

Patents

Dr. Safar holds 27 US and Europeans patents, including one for a method for detecting 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).

Publications

Dr. Safar is the author of 189 publications, including 99 peer-reviewed 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 17 years (Cited 773-times, Institute for Scientific Information, 1998-2015).

Selected Peer Reviewed Journal Articles and Book Chapters

Mays CE, Kim C, Haldiman T, van der Merwe J, Lau A, Yang J, Grams J, Di Bari MA, Nonno R, Telling GC, Kong Q, Langeveld J, McKenzie D, Westaway D, Safar JG. (2014) Prion disease tempo determined by host-dependent substrate reduction. J Clin Invest. 2014 Jan 16. pii: 72241. doi: 10.1172/JCI72241. PMID: 24430187

Haldiman T, Kim C, Cohen Y, Chen W, Blevins J, Qing L, Cohen ML, Langeveld J, Telling GC, Kong Q, Safar JG. (2013) Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection. J Biol Chem. 2013 Oct 11;288(41):29846-61. PMID: 23974118

Kim, C., Haldiman,T., Surewicz, K., Cohen, Y., Chen, W., Blevins, J., Sy, M-S., Cohen, M., Kong, Q., Telling, G.C., Surewicz, W.K., and Safar, J.G. (2012) Small Protease Sensitive Oligomers of PrP(Sc) in Distinct Human Prions Determine Conversion Rate of PrP(C). PLoS Pathog. 2012 Aug;8(8):e1002835. Epub 2012 Aug 2. PMID: 22876179

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.

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., 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.

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.

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

Safar, J.G. (2012) Molecular Mechanisms Encoding Quantitative and Qualitative Traits of Prion Strains. In: Prions and Prion Diseases, eds. P. Gambetti and W. Zou, Springer-Verlag, New York, Berlin, Heidelberg, Tokyo, 161-179.

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.

Journal Review Articles

Kabir ME, Safar JG. (2014) Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases. Prion. 2014 Jan 8;8(1). PMID: 24401672

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