Research Abstract:
Prion diseases, including Creutzfeldt-Jakob disease and kuru, are fatal neurodegenerative disorders that are now of great medical importance because of emergence of “mad cow disease” in Europe and the U.S., and its likely transmission to human beings. These diseases are also of enormous scientific interest because they involve an entirely novel mechanism of biological information transfer: they result from a change in the conformation of an endogenous membrane glycoprotein (PrPC) which converts it into a pathogenic isoform (PrPSc) that is infectious in the complete absence of nucleic acid.
My laboratory is interested in understanding prion diseases at the cellular and molecular levels. We are investigating a number of interrelated questions, including: How is PrPC is converted into PrPSc? How are these forms processed and targeted in cells? What other proteins do they interact with? What is the normal function of PrPC? How do prions kill cells, and what forms of PrP are responsible? To address these issues, we utilize several experimental systems including yeast, cultured mammalian cells, and transgenic mice. We employ a wide range of techniques, including cell labeling, protein chemistry, light and electron microscopy, proteomics, DNA microarray analysis, mouse genetics, neuropathology, and animal bioassays.
Selected Publications:
Medrano AZ, Barmada SJ, Biasini E, Harris DA. GFP-tagged mutant prion protein forms intra-axonal aggregates in transgenic mice. Neurobiol Dis 2008 31: 20-32.
Biasini E, Seegulam ME, Patti BN, Solforosi L, Medrano AZ, Christensen HM, Senatore A, Chiesa R, Williamson RA, Harris DA. Non-infectious aggregates of the prion protein react with several PrPSc-directed antibodies. J Neurochem 2008 105: 2190-2204.
Li A, Christensen HM, Stewart LR, Roth KA, Chiesa R, Harris DA. Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125. EMBO J 2007 26: 548-558.
Li A, Piccardo P, Barmada SJ, Ghetti B, Harris DA. Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice. EMBO J 2007 26: 2777-2785.
Harris DA, True HL. New insights into prion structure and toxicity. Neuron 2006 50: 353-357.
Last Updated: 08/27/2009 |