Project 3 DeGrado An expanding body of evidence argues that besides PrP, A, tau and synuclein can become prions and cause neurodegeneration. We seek to understand the assembly of prion precursors into oligomers and fibers, and to correlate the formation of specific conformational forms with toxicity and transmissibility. The small size of A makes it an attractive molecule to study with respect to conversion into prions that are presumably oligomers. We propose to determine the steps required for A to acquire a self-propagating conformation that templates the assembly of additional monomers into oligomers and possibly fibers. The molecular structures of the key intermediates in this process are poorly understood, and it is not known whether the transmissible particle has the parallel cross-beta structure seen in fibers. While it is generally accepted that A oligomers rather than fibers represent the toxic species, the relationship between toxicity and the size, conformation, and dynamics of the oligomers is unknown. We will develop new chemical tools to probe and dissect the steps of aggregation and amyloid formation. We will develop novel chemical strategies to rapidly trigger A association and follow the evolution of its conformation over time. We also will design peptide mimetics and foldamers that enhance or inhibit assembly by stabilizing specific intermediates, allowing one to obtain better defined populations for building correlations between structure, transmissibility and toxicity. Finally, we will develop crosslinking strategies that can be used to obtain a footprint of the conformational ensemble of synthetic versus natural A, PrP, and tau at various levels of assembly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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University of California San Francisco
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Giles, Kurt; Woerman, Amanda L; Berry, David B et al. (2017) Bioassays and Inactivation of Prions. Cold Spring Harb Perspect Biol 9:
Woerman, Amanda L; Watts, Joel C; Aoyagi, Atsushi et al. (2017) ?-Synuclein: Multiple System Atrophy Prions. Cold Spring Harb Perspect Med :
Stöhr, Jan; Wu, Haifan; Nick, Mimi et al. (2017) A 31-residue peptide induces aggregation of tau's microtubule-binding region in cells. Nat Chem 9:874-881
Lopez, T Peter; Giles, Kurt; Dugger, Brittany N et al. (2017) A novel vector for transgenesis in the rat CNS. Acta Neuropathol Commun 5:84
Lee, Myungwoon; Wang, Tuo; Makhlynets, Olga V et al. (2017) Zinc-binding structure of a catalytic amyloid from solid-state NMR. Proc Natl Acad Sci U S A 114:6191-6196
Watts, Joel C; Prusiner, Stanley B (2017) ?-Amyloid Prions and the Pathobiology of Alzheimer's Disease. Cold Spring Harb Perspect Med :
Saltzberg, Daniel J; Broughton, Howard B; Pellarin, Riccardo et al. (2017) A Residue-Resolved Bayesian Approach to Quantitative Interpretation of Hydrogen-Deuterium Exchange from Mass Spectrometry: Application to Characterizing Protein-Ligand Interactions. J Phys Chem B 121:3493-3501
Adler, C H; Beach, T G; Shill, H A et al. (2017) GBA mutations in Parkinson disease: earlier death but similar neuropathological features. Eur J Neurol 24:1363-1368
Gerkin, Richard C; Adler, Charles H; Hentz, Joseph G et al. (2017) Improved diagnosis of Parkinson's disease from a detailed olfactory phenotype. Ann Clin Transl Neurol 4:714-721
Giles, Kurt; Olson, Steven H; Prusiner, Stanley B (2017) Developing Therapeutics for PrP Prion Diseases. Cold Spring Harb Perspect Med 7:

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