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James A. Mastrianni, M.D., Ph.D.
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Education:
Research SummaryMy laboratory's research is aimed at understanding the prion diseases. Perhaps best known as the cause of Mad Cow Disease, prions also cause several other brain disorders, including Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, fatal insomnia, and chronic wasting disease of deer and elk. These unusual disorders have many similarities with neurodegenerative diseases, as they cause progressive neurological symptoms of dementia and motor abnormalities, but they differ in that they carry the property of infectivity. The infectious agent of these diseases is an unconventional agent, called a prion, which is thought to be composed entirely of protein. The protein that constitutes the prion is the prion protein, a host-encoded, predominantly brain-derived protein. The prion protein becomes infectious by that has become misfolded. This protein is a naturally-occurring brain-derived protein that undergoes a conformational change, resulting in the generation of an 'infectious' protein that binds to and converts other normal prion proteins to prions. My lab is investigating several aspects of prions and prion disease, including what segments of the protein are critical to the process of prion propagation and conformational conversion, how specific mutations of the protein that are associated with familial prion disease produce prions, how different strains or phenotypes of prion disease are determined by the prion, how prions kill cells, and what other proteins may partner with prion protein to cause or modify prion disease. A variety of experimental approaches are utilized from cell culture, transgenic mouse models, yeast models, and organotypic brain slice preparations, in order to better understand these enigmatic diseases. Our findings will help clarify how brain neurons die in prion diseases as well as other neurodegenerative diseases, such as Alzheimer's disease and ALS. Selected PublicationsTelling, G. Scott, M., Mastrianni, J., Gabizon,
R., Torchia, M., Cohen,
F., DeArmond, S., and Prusiner, S. Prion Propagation in Mice
Expressing
Human and Chimeric PrP Transgenes Implicates the Interaction of
Cellular
PrP with Another Protein. Cell, 83(1):
79-90, 1995.
Mastrianni, J.A., Curtis, M.T., Oberholtzer, J.C., Prusiner, S.B., and J.Y. Garbern: Ataxic Gerstmann-Straussler-Scheinker Diseased Caused by a Prion Protein Gene Mutation at Codon 117. Neurology, 45(11), pp.2042 - 2050, 1995. Mastrianni, J.A., Iannocola, C., Myers, R., and S.B.Prusiner: Mutation of the Prion Protein Gene at Codon 208 in Familial Creutzfeldt-Jakob disease. Neurology, 47(4), pp. 1305-1312, 1996. Telling, G., Parchi, P., DeArmond, S., Cortelli, P., Montagna, P., Gabizon, R., Mastrianni, J., Lugaresi, E., Gambetti, P., and Prusiner, S.: Evidence for the Conformation of the Pathologic Isoform of the Prion Protein Enciphering and Propagating Prion Diversity. Science, 274, pp:2079-2082, December 20, 1996. Hegde, R.S., Mastrianni, J.A., Scott, M.R., DeFea, K.A., Tremblay, P., Torchia, M., DeArmond, S., Prusiner, S.B., and Lingappa, V.R.: A Transmembrane Form of the Prion Protein in Neurodegenerative Disease. Science, 6, 279(5352):827-34, Feb., 1998. Mastrianni, J.A., Nixon, R., Layzer, R., DeArmond, S., and Prusiner, S.B., Prion Protein Conformation in a Patient with Sporadic Fatal Insomnia. N. Eng. J. Med., May 27;340(21):1630-8, 1999. Podulslo, S.E., Yin, X., Hargis, J., Brumback, R.A., Mastrianni, J.A. and Schwankhaux, J. A familial case of Alzheimer's disease without tau pathology may be linked with chromosome 3 markers. Human Genetics, 105:32-37, 1999. Mastrianni J.A., Capellari, S., Telling, G.C., Han, D., Bosque, P., Prusiner, S.B. and DeArmond, S.J. Inherited prion disease caused by the V210I mutation: Transmission to transgenic mice, Neurology, 26:57(12):2198-2205, 2001. Korth, C., Kaneko, K., Groth, D., Heye, N., Telling, G., Mastrianni, J., Parchi, P., Gambetti, P., Will, R., Ironside, J., Heinrich, C., Tremblay, P., DeArmond, S.J. and Prusiner, S.B. Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene. Proc. Natl. Acad. Sci. U.S.A., Apr 8, 2003. |
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