James Mastrianni, M.D., Ph.D.

Research Summary

My laboratorys 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 Alzheimers disease and ALS.

Selected Papers

Telling G, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen F, DeArmond S and Prusiner S. (1995). Prion Propagation in Mice Expressing Human and Chimeric PrP Transgenes Implicates the Interaction of Cellular PrP with Another Protein, Cell 83(1): 79-90.

Mastrianni JA, Curtis MT, Oberholtzer JC, Prusiner SB and Garbern JY. (1995). Ataxic Gerstmann-Straussler-Scheinker Diseased Caused by a Prion Protein Gene Mutation at Codon 117, Neurology 45(11), pp.2042 - 2050.

Mastrianni JA, Iannocola C, Myers R and SB Prusiner. (1996). Mutation of the Prion Protein Gene at Codon 208 in Familial Creutzfeldt-Jakob disease, Neurology 47(4), pp. 1305-1312.

Telling G, Parchi P, DeArmond S, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P and Prusiner S. (1996). Evidence for the Conformation of the Pathologic Isoform of the Prion Protein Enciphering and Propagating Prion Diversity, Science 274, pp:2079-2082, December 20.

Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M, DeArmond S, Prusiner SB and Lingappa VR. (1998). A Transmembrane Form of the Prion Protein in Neurodegenerative Disease, Science,.6, 279(5352): 827-34.

Mastrianni JA, Nixon R, Layzer R, DeArmond S and Prusiner SB. (1999). Prion Protein Conformation in a Patient with Sporadic Fatal Insomnia, N Eng J Med., May 27;340(21):1630-8.

Podulslo SE, Yin X, Hargis J, Brumback RA, Mastrianni JA and Schwankhaux J. (1999). A familial case of Alzheimers disease without tau pathology may be linked with chromosome 3 markers, Human Genetics, 105:32-37.

Mastrianni JA, Capellari S, Telling GC, Han D, Bosque P, Prusiner SB, DeArmond SJ. (2001). Inherited prion disease caused by the V210I mutation: Transmission to transgenic mice, Neurology 26;57(12):2198-2205.

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 SJ, Prusiner SB. (2003). Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene. Proc Natl Acad Sci U S A.