Molecular & Protein Structural
Studies of Prion Disease
My research has focused on an unprecedented class of Pathogens called Prions which cause NeuroDegenerative Diseases. Nascent Prions are created either spontaneously by mutation of a host protein or by exposure of the latter to Prions from an exogenous source.
Prions are composed largely, if not entirely, of a modified form of the Prion protein (PrP) designated PrPSc, yet they can multliply without a Nucleic Acid genome.
A post-translational, conformational change features in the conversion of cellular PrP (PrPC) into PrPSc in which - helices are transformed into - sheets.
Since this structural transition in PrP underlies both the replication of Prions and the PathoGenesis of CNS degeneration, much of the effort in the laboratory is devoted to elucidating the molecular events responsible for this process.
Indeed, Prion Diseases seem to be disorders of protein conformation.
After demonstrating Genetic linkage between the PrP Gene and the control of scrapie incubation times, we established linkage between a human PrP Gene point mutation and development of the fatal, Familial Disease Gerstmann-Straussler-Scheinker (GSS).
Like humans with GSS, transgenic mice expressing mutant PrP develop NeuroDegeneration and produce Prions de novo as demonstrated by transmission of disease to inoculated recipients.
These studies argue that Prion Diseases can be both inherited and infectious.
While PrPSc seems to act as a template for the refolding of PrPC into a second molecule of PrPSc, we recently discovered that formation of PrPSc involves another molecule which restricts Prion replication between distant species.
To overcome this restriction, we constructed chimeric human/mouse PrP transgenes; mice expressing this hybrid Gene were rendered highly susceptible to human Prions.
This discovery opens many new investigations of the human Prion Diseases that previously required apes or monkeys.
Identifying the molecule(s), provisionally designated protein X, that participate in the conversion of PrPC into PrPSc is another area of research in the laboratory.
Prions exhibit different patterns of disease which mimic strains of viruses where diversity is encoded within the Viral genome.
Elucidating the mechanism of Prion diversity is a third area of investigation. Whether strains of Prions represent distinct conformers of PrPSc or a second, as yet unidentified, molecule features in this process is unknown.
Sci Am 272:70-77, 1995
The Prion Diseases
Telling, G.C., Scott, M., Hsiao, K.K., Foster, D., Yang, S.-L.l, Torchia, M., Sidle, K.C.L., Collinge, J., DeArmond, S.J., Prusiner, S.B.
Proc. Natl. Acad. Sci. USA 91:9936-9940, 1994
Transmission of Creutzfeldt-Jakob Disease from Humans to Transgenic Mice Expressing Chimeric Human-Mouse Prion Protein
Cohen, F.E., Pan, K.-M., Huang, Z., Baldwin, M., Fletterick, R.J., Prusiner, S.B.
Science 264:530-531, 1994
Structural Clues to Prion Replication
Westaway, D., DeArmond, S.J., Cayetano-Canlas, J., Groth, D., Foster, D., Yang, S.-L., Torchia, M., Carlson, G.A., Prusiner, S.B.
Cell 76:117-129, 1994
Degeneration of Skeletal Muscle, Peripheral Nerves, & the Central Nervous System in Transgenic Mice Overexpressing Wild-Type Prion Proteins
Carlson, G.A., Ebeling, C., Yang, S.-L., Telling, G., Torchia, M., Groth, D., Westaway, D., DeArmond, S.J., Prusiner, S.B.
Proc. Natl. Acad. Sci. USA 91:5690-5694, 1994
Eveidence for Isolate Specified Allotypic Interactions Between the Cellular & Scrapie Prion Proteins in Congenic & Transgenic Mice