Amyloids are misfolded proteins that are structurally similar to and include prions.'Amyloids are implicated in the pathogeneis of more than 40 different diseases including the common neurodegenerative disorders Alzheimer's and Parkinson's diseases. The long-term goals of this project include characterization of the pathways leading to amyloid formation and disease pathology, in order to guide the development of improved therapeutic and diagnostic approaches to the prion diseases and other amyloidoses. In the infectious amyloidoses caused by prions, the prion protein (PrP) folds into aberrant conformation denoted PrPSc. The infectious prion particle is comprised solely of PrPSc molecules in mammals. Prion diseases include Creutzfeldt-Jakob disease (CJD) and related hereditary disorders as well as the infectious human maladies variant CJD and kuru. The animal prion diseases include bovine spongiform encephalopathy (""""""""mad cow disease""""""""), scrapie in sheep and chronic wasting disease in deer. Our studies using X-ray fiber diffraction and a variety of complementary techniques are aimed at determining the molecular structures of several different amyloids. The first group of amyloids comprise peptides derived from non-infectious amyloids. These are more tractable for structural analysis, and will serve as models for prion structure. These polypeptides include those associated with Alzheimer's, Huntington's, and several other diseases. The second group is composed of amyloidogenic peptides derived from prions;these include a 55-residue fragment of the prion protein harboring the PrP mutation P102L that causes Gerstmann-Straussler- Scheinker disease. The third group includes the purified N-terminally truncated and full-length PrPSc that are infectious. These will be isolated from scrapie-infected mouse and hamster brains. Structure determination will require the construction of molecular models, and the development and refinement of these models using data from X-ray fiber difraction. Electron microscopy will provide low-resolution constraints on molecular models;where available, published partial structure information from X-ray crystallography or solid state NMR will be incorporated. Published models, which are generally in marked disagreement with each other, will be evaluated.
Fiber diffraction effectively bridges the gap between the low resolution of electron microscopy and the high resolution of crystallography and ssNMR, allowing the construction and refinement of models that include useful information at all structural levels.
|Tuttle, Marcus D; Comellas, Gemma; Nieuwkoop, Andrew J et al. (2016) Solid-state NMR structure of a pathogenic fibril of full-length human Î±-synuclein. Nat Struct Mol Biol 23:409-15|
|Watts, Joel C; Giles, Kurt; Saltzberg, Daniel J et al. (2016) Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions. J Virol 90:9558-9569|
|Watts, Joel C; Giles, Kurt; Bourkas, Matthew E C et al. (2016) Towards authentic transgenic mouse models of heritable PrP prion diseases. Acta Neuropathol 132:593-610|
|Ahlenius, Henrik; Chanda, Soham; Webb, Ashley E et al. (2016) FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice. Proc Natl Acad Sci U S A 113:8514-9|
|Giles, Kurt; Berry, David B; Condello, Carlo et al. (2016) Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice. J Pharmacol Exp Ther 358:537-47|
|Elkins, Matthew R; Wang, Tuo; Nick, Mimi et al. (2016) Structural Polymorphism of Alzheimer's Î²-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. J Am Chem Soc 138:9840-52|
|Woerman, Amanda L; Aoyagi, Atsushi; Patel, Smita et al. (2016) Tau prions from Alzheimer's disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc Natl Acad Sci U S A 113:E8187-E8196|
|Lu, Jonathan; Trnka, Michael J; Roh, Soung-Hun et al. (2015) Improved Peak Detection and Deconvolution of Native Electrospray Mass Spectra from Large Protein Complexes. J Am Soc Mass Spectrom 26:2141-51|
|Tousseyn, Thomas; Bajsarowicz, Krystyna; SÃ¡nchez, Henry et al. (2015) Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes. J Neuropathol Exp Neurol 74:873-88|
|Shanmugasundaram, Maruda; Kurouski, Dmitry; Wan, William et al. (2015) Rapid Filament Supramolecular Chirality Reversal of HET-s (218-289) Prion Fibrils Driven by pH Elevation. J Phys Chem B 119:8521-5|
Showing the most recent 10 out of 344 publications