Molecular basis of prion diseases and other neurodegenerative disorders associated with protein misfolding
The prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders that include scrapie in sheep, mad cow disease in cattle, and kuru, Creutzfeldt-Jakob disease, GSS disease and fatal familial insomnia in humans. Pathogenesis in these unusual diseases is associated with a conformational rearrangement of the cellular prion protein (PrPc) to an abnormal "scrapie" conformer, PrPSc. While the benign PrPc conformer is monomeric and rich in alpha-structure, PrPSc is a protein aggregate (often amyloid) characterized by an increased proportion of ß-structure and resistance to proteolytic digestion. Although molecular details of the pathogenic process in TSE diseases remain controversial, a growing body of evidence supports the protein-only model, according to which PrPSc itself is the infectious prion pathogen. PrPSc is believed to self-perpetuate by a unique mechanism involving binding to PrPc and inducing a conversion of the latter protein to the PrPSc state. The notion that an infectious agent can be devoid of nucleic acids and propagate by a mechanism based on self-perpetuating changes in protein conformation constitutes a new paradigm in molecular biology and medicine.
Our group is interested in biophysical and biochemical aspects of prion protein folding/misfolding and the molecular basis of prion strains and TSE transmissibility barriers. The current focus of our research is on (i) Elucidating the molecular mechanisms and structural basis of PrP conformational conversion; (ii) Determining structural determinants of prion infectivity; (iii) Understanding the role of non-proteinaceous cofactors in prion protein conversion to the infectious form; (iv) Understanding the molecular/structural basis of prion strains and TSE transmissibility barriers. Methodologically, this research constitutes a combination of state-of-the-art methods of protein chemistry, structural biology and studies using transgenic mice.
Apart from prion reseach, our laboratory has an active research program in the area of Alzheimer’s disease (AD), the most common neuodgenerative disease of aging. The pathogenic process in AD appears to be closely linked to the neurotoxic action of amyloid-ß (Aß) oligomers. We are especially interested in the postulated role of the normal form of the prion protein (PrP) as a mediator of neurotoxicity of Aß oligomers, and our current efforts focus on development of PrP-based compounds as potential therapeutic agents in AD. We are also interested in the role of structural polymorphism of Aß and tau aggregates as a potential determinant of phenotypic variability in AD.
- Jones EM & WK Surewicz. Fibril conformation as the basis of species- and strain-dependent seeding specificity of mammalian prion amyloids. Cell 121:63-72, 2005.
- Cobb NJ, FD Sönnichsen, H McHaourab & WK Surewicz. Molecular architecture of human prion protein amyloid: a parallel, in-register beta-structure. Proc. Natl. Acad. Sci. U.S.A. 104:18946-51, 2007.
- Smirnovas V, GS Baron, DK Offerdahl, GJ Raymond, B Caughey & WK Surewicz. Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange. Nat. Struct. Mol. Biol. 18:504-6, 2011.
- Kong Q, JL Mills, B Kundu, X Li, L Qing, K Surewicz, I Cali, S Huang, M Zheng, W Swietnicki, FD Sönnichsen, P Gambetti & WK Surewicz. Thermodynamic stabilization of the folded domain of prion protein inhibits prion infection in vivo. Cell Rep 4:248-54, 2013.
- Safar JG, X Xiao, ME Kabir, S Chen, C Kim, T Haldiman, Y Cohen, W Chen, ML Cohen & WK Surewicz. Structural determinants of phenotypic diversity and replication rate of human prions. PLoS Pathog. 11:e1004832, 2015.
- Scott-McKean JJ, K Surewicz, JK Choi, VA Ruffin, AI Salameh, K Nieznanski, AC Costa & WK Surewicz. Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by A? oligomers: Implications for novel therapeutic strategy in Alzheimer's disease. Neurobiol. Dis. 91:124-31, 2016.