Prion diseases, such as Creutzfeldt-Jakob Disease (CJD), are degenerative disorders affecting the central nervous system. They are uniformly fatal and illicit death following a long period of steady neurodegeneration, dementia and motor disfunction. In prion diseases, an aberrantly folded conformer ofthe prion protein (PrPSc) propagates by catalyzing the post-translational misfolding of cellular PrP (PrPC). We have recently succeeded in recapitulating this phenomenon in vitro by converting purified, bacterially-expressed, recombinant PrP into infectious prions. The ability to create synthetic prions in cell-free systems has provided definitive proof of the protein-only hypothesis of prion propagation and has enabled us to begin deciphering the structural basis of protein-based infectivity.
The specific aims of this project seek to utilize synthetic prions to gain insights into the mechanism of prion-induced neurodegeneration. We propose to create homogeneous and highly infectious preparations of synthetic prions. The synthetic prion preparations will be propagated in mouse bioassays and used for structural analyses. Disease phenotypes induced by synthetic prions will be assessed by two novel approaches for global analysis of proteome homeostasis. Effects on protein translation will be studied by ribosome profiling and changes in proteome turnover will be measured by comprehensive in vivo isotopic replacement. We will also attempt to infect induced neuronal (iN] cells with synthetic prions. These strategies will uncover relationships between the physical structure of prion strains and their biological properties and may provide valuable insights into the mechanism of neurodegeneration in prion diseases such as CJD.
The continuing aging ofthe American population has made the discovery of therapies against neurodegenerative disorders an important public health goal. This study will provide insight into the etiology of prion diseases such as Creutzfeldt-Jakob disease (CJD), and may illuminate the mechanism of neurodegeneration in more prevalent proteinopathies such as Alzheimer's disease and Parkinson's disease.
|Lim, Kwang Hun; Dasari, Anvesh K R; Hung, Ivan et al. (2016) Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR. Biochemistry 55:1941-4|
|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|
|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|
|Dunn, Joshua G; Weissman, Jonathan S (2016) Plastid: nucleotide-resolution analysis of next-generation sequencing and genomics data. BMC Genomics 17:958|
|Patzke, Christopher; Acuna, Claudio; Giam, Louise R et al. (2016) Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation. J Exp Med 213:499-515|
|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|
|Lim, Kwang Hun; Dasari, Anvesh K R; Hung, Ivan et al. (2016) Solid-State NMR Studies Reveal Native-like ?-Sheet Structures in Transthyretin Amyloid. Biochemistry 55:5272-8|
|Elkins, Matthew R; Wang, Tuo; Nick, Mimi et al. (2016) Structural Polymorphism of Alzheimer's ?-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. J Am Chem Soc 138:9840-52|
|Wan, William; Stöhr, Jan; Kendall, Amy et al. (2015) Truncated forms of the prion protein PrP demonstrate the need for complexity in prion structure. Prion 9:333-8|
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