Abstract
Two processes lie at the heart of protein misfolding diseases such as Creutzfeldt-Jacob, Parkinson’s, and Alzheimer’s disease: the conversion of protein into misfolded, toxic structures, and their replication by a prion-like mechanism (1-3). A main obstacle in understanding their molecular mechanism is the lack of tools to see and differentiate amyloid structures. We have developed a new super-resolution microscopy technique (TAB) to visualize amyloid on a nanometer scale. Dye molecules bind to amyloid with defined orientations and can distinguish between amyloid species. This project will develop this technique to analyze structure, toxicity, and structural dynamics of prion replication.
References
1. Haass, C. and D.J. Selkoe, Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol, 2007. 8(2): p. 101-12.
2. Harper, J.D. and P.T. Lansbury, Jr., Models of amyloid seeding in Alzheimer’s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem, 1997. 66: p. 385-407.
3. Prusiner, S.B., Prions. Proc Natl Acad Sci U S A, 1998. 95(23): p. 13363-83.
4. Sandberg, M.K., et al., Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature, 2011. 470(7335): p. 540-2.
5. Wenborn, A., et al., A novel and rapid method for obtaining high titre intact prion strains from mammalian brain. Sci Rep, 2015. 5: p. 10062.
6. Terry, C., et al., Ex vivo mammalian prions are formed of paired double helical prion protein fibrils. Open Biol, 2016. 6(5).