Dr. Safar 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. He invented the Conformation-Dependent Immunoassay (CDI) for detection, and Conformational Stability Assay (CSA) for differentiation of prions and prion-like proteins, including those causing Alzheimer’s disease, and synthesized the first artificial human prion. The new concept for detection prions and other misfolded proteins was patented internationally, and the CDI was validated for diagnosis of Creutzfeldt-Jacob Disease, and animal diseases (BSE, scrapie) in European Union.
After completing his residency, chief residency, and PhD training in Biochemistry, Dr. Safar received Research Fellowship in the Laboratory of Central Nervous System Studies at the National Institutes of Health (NIH), 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 the conformational transition, and he introduced a novel concept of the folding intermediate as a crucial stage in the prion formation. For this groundbreaking research, he received the National Institutes of Health Merit Award.
In 1996, he took a position of Senior Scientist at the Institute for Neurodegenerative Diseases, directed by Stanley B. Prusiner (Nobel Prize for Medicine 1997), and position of Associate Professor at the University of California at San Francisco (UCSF). He discovered new oligomeric forms of prions and led a team that developed a new concept for detection and differentiation of prions exploiting differences in their structural organization.
In 2008, Dr. Safar was offered to establish a new research laboratory at the Department of Pathology, Case Western Reserve University (CWRU). The Safar lab basic and translational research targets three crucial problems of structural biology of age-related neurodegenerative disorders caused by prions and prion-like proteins including Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and human prion diseases such as Creutzfeldt-Jakob disease (CJD).
Dr. Safar holds 27 US and European patents including one for a method for detecting misfolded proteins (Prusiner, S.B., Safar J. (1999) US Patent #5,891,641), and one for device that removes prions from blood, plasma, and other liquids (Prusiner, S.B., Safar J., (2001) US Patent #6,221,614 B1).
My areas of research include protein misfolding, structure-function correlations, amyloid immunochemistry, age-related neurodegeneration, transgenic mice therapeutics, translational medicine, prion diseases, and Alzheimer’s disease.
Graduate Training Opportunities in Safar Lab
PhD Program in Basic and Translational Neurobiology and Neuroscience of Human Neurodegenerative Diseases
Safar Laboratory at the Department of Pathology offers graduate training in a wide range of projects in advanced neurobiology and neuroscience. The graduate program has a strong emphasis on cellular and molecular mechanisms of human neurodegenerative diseases such as Alzheimer’s, Frontotemporal dementia, and prion diseases. Training in neurobiology and neuroscience is provided through a combination of CWRU course work, research, and seminars.
Thesis research opportunities are available in areas such as impact of misfolded proteins and prions on synaptic function and plasticity; mechanism of misfolded protein and prion replication and propagation in neurons, human brain aging; protein/protein interactions in the human brain and neuronal models of human diseases; human brain proteomics; and structural studies of neuronal proteins.
The Department of Pathology is an attractive training environment with the highly interactive atmosphere, characterized by extensive collaboration among laboratories and with other departments, specifically Dept of Physiology and Biophysics, Department of Department of Neurology, and Department of Neuroscience.
Safar Lab has a leading expertise in the following areas:
- Age-Related Neurodegenerative Disorders Caused by Protein Misfolding;
- Advanced Detection and Differentiation of Prions and Other Misfolded Proteins;
- Neuronal and Transgenic Models of Alzheimer’s disease, Frontotemporal dementia, and prion diseases;
- Proteomics and High-Resolution Structural Biochemistry of Neuronal Proteins;
- Replication and Propagation Mechanism of Prions and Prion-Like Proteins in Nervous System.
Some reasons why you should consider our PhD program:
- The Case Western Reserve University School of Medicine has an outstanding research reputation nationally and internationally;
- Department of Pathology has three NIH-funded T32 training programs in Molecular and Cellular Basis of Disease, T32 Medical Scientist Training Program, and TL1 Clinical and Translational Scientist Training Program;
- Safar Lab has a long history of NIH grant funding support and extensive publication record in high ranking journals;
- Case Western Reserve University PhDs move to highly competitive positions;
- The strong environment for training with easy faculty-student interactions and good cross department/cross-discipline collaborations;
Cleveland is a graduate student friendly place, the cost of living is low, nice housing is very close to the university, and there are exciting activities at the university, in the city and in the surrounding area.
*More information and how and where to apply is in the link below:
The Molecular Basis of Age-Related Dementias
The Safar Lab developed a battery of ultrasensitive new tools for investigating the mechanism of misfolding of major proteins causing AD, AD-related dementias (ADRD), and prion diseases directly in human brains. Through methods such as conformation-dependent immunoassay (CDI), conformational stability assay (CSA), conformation-sensitive mass spectroscopy (MS), fluorescence spectroscopy, and cryo-Electron Microscopy (cryo-EM), the laboratory ultimate goal is to elucidate the structure of disease-causing distinct misfolded forms — strains — of human brain-derived amyloid beta, tau, and prions.
The Role of Prion-Like Strains of Misfolded Proteins in Phenotypic Diversity of Neurodegeneration
Using human brain isolates, transgenic models, and cell cultures, these projects focus on improving our understanding of the molecular mechanisms governing the phenotypic heterogeneity and progression rates of AD and prion diseases, specifically on different prion-like strains of small oligomers (SOs) of Amyloid beta, tau, and pathogenic prion protein.
The Interactomes of Prion-Like Strains of Misfolded Proteins on Distinct Genetic Backgrounds
The goal of these studies is to delineate the impact of prion-like strains of amyloid beta and tau upon the AD phenotype in the context of specific risk genes using proteomic profiling of amyloid plaques, neurofibrillary tangles, glia, and neurons. This insight is critical for efforts to characterize key factors responsible for the very rapid rate of cognitive decline in some subtypes of AD and ultimately to novel therapeutic strategies to slow AD progression.
Awards and Honors
- 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
- Editorial boards of Prion (UK), and Frontiers in Aging Neuroscience Journal (Switzerland)
Dr. Safar is the author of 132 peer-reviewed papers, reviews, and book chapters encompassing a broad range of research in conformational protein chemistry, neuroscience, molecular biology, immunology, and neurodegeneration in humans and animal models. His paper in Nature Medicine is the most cited original work on prions published in the past 20 years (Safar J. et al., Nature Medicine 1998, cited 923-times; Institute for Scientific Information).
Selected Peer Reviewed Articles
- Kim C, Xiao X, Chen S, Haldiman T, Smirnovas V, Kofskey D, Warren M, Surewicz K, Maurer NR, Kong Q, Surewicz W, Safar JG (2018) Artificial strain of human prions created in vitro. Nature Communications 9(1):2166. doi: 10.1038/s41467-018-04584-z. PMCID: PMC5986862.
- Cohen ML, Kim C, Haldiman T, ElHag M, Mehndiratta P, Pichet T, Lissemore F, Shea M, Cohen Y, Chen W, Blevins J, Appleby BS, Surewicz K, Surewicz WK, Sajatovic M, Tatsuoka C, Zhang S, Mayo P, Butkiewicz M, Haines JL, Lerner AJ, Safar JG. (2015) Rapidly Progressive Alzheimer Disease Features Distinct Structures of β-Amyloid. Brain: Epub 2015/02/18. PMID: 25688081.
- Safar JG, Xiao X, Kabir ME, Chen S, Kim C, Haldiman T, Cohen Y, Chen W, Cohen ML, Surewicz WK. (2015) Structural determinants of phenotypic diversity and replication rate of human prions. PLoS Pathog. 2015 Apr 14;11(4):e1004832. doi: 10.1371/journal.ppat.1004832. eCollection 2015. PMCID: PMC4397081.
- 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; 124(2):847-58. PMCID: PMC3904628.
- 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. PMCID: PMC37952833.
- 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. PMCID: PMC3410855.
- 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. PMCID: PMC552933.
- 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. PMID: 16186247.
- 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. PMID: 12389035.
- 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. PMID: 9771749.