Overall In four scientific projects and four cores, we propose to study A PrP, and tau prions causing neurodegeneration. The discovery that prions cause Alzheimer's disease and other neurodegenerative diseases including frontotemporal dementias, Parkinson's disease, and ALS opens new research strategies for deciphering the pathogenesis of these illnesses and developing novel therapeutic approaches. Fundamental to understanding all prions is defining the structural transition that a particular protein undergoes when it becomes a prion. In this P01 renewal application, we plan to exploit new data published by us and others contending that A and tau, like PrP, can acquire conformations that are self-propagating; thus, they are prions. In each case, these alternative conformations are enriched for -sheet structure and readily polymerize in amyloid fibrils that often condense into plaques r tangles. In Project 1, we propose to study the properties of strains of A prions using bigenic mice that we created, to develop cultured cell bioassays that can detect A and tau prions, to investigate human (Hu) PrP prions using bigenic mice expressing bank vole (BV) PrP or chimeric Hu/BVPrP transgenes, and to determine if cultured cells expressing BVPrP can support the replication of human prion strains. In Project 2, we propose to continue structural studies of PrPSc formed from recombinant PrP utilizing an 89-mer fragment that initiated replication of anchorless PrPSc prions, to continue structural studies of A with emphasis on naturally occurring mutants, and to initiate structural studies of tau prions. In Project 3, we propose to determine the structure of A prions by solution and solid-state NMR; to monitor A assembly using multiple probes that are sensitive to both global and local conformations; to create thioamide- containing peptides and foldamers that enhance or inhibit individual steps of amyloid initiation, elongation, and fragmentation; and to synthesize a series of crosslinking reagents to probe the distribution of distances between Lys and Arg residues in A, PrP and tau prions. In Project 4, we propose to adapt and apply integrative structural modeling to protein self-assembly, thus facilitating simultaneous modeling of multiple structural states based on sparse, noisy, ambiguous and incoherent data of different kinds.
Overall it is estimated that ~36 million people suffer from neurodegenerative diseases; as the baby boomer generation continues to age, an estimated 120 million people will suffer worldwide from some form of dementia by 2050. The current annual cost of Alzheimer's disease (AD) in the US is ~$200 billion, and there is not a single drug that halts or even slows the disease. Mounting evidence argues that AD is caused by two proteins, A and tau, that adopt alternative shapes and become prions; it is urgent that we define the molecular pathogenesis of AD in order to create effective therapeutics.
| Irimata, Katherine E; Dugger, Brittany N; Wilson, Jeffrey R (2018) Impact of the Presence of Select Cardiovascular Risk Factors on Cognitive Changes among Dementia Subtypes. Curr Alzheimer Res 15:1032-1044 |
| Nick, Mimi; Wu, Yibing; Schmidt, Nathan W et al. (2018) A long-lived A? oligomer resistant to fibrillization. Biopolymers 109:e23096 |
| Woerman, Amanda L; Watts, Joel C; Aoyagi, Atsushi et al. (2018) ?-Synuclein: Multiple System Atrophy Prions. Cold Spring Harb Perspect Med 8: |
| Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) Familial Parkinson's point mutation abolishes multiple system atrophy prion replication. Proc Natl Acad Sci U S A 115:409-414 |
| O'Brien, Connor J; Droege, Daniel G; Jiu, Alexander Y et al. (2018) Photoredox Cyanomethylation of Indoles: Catalyst Modification and Mechanism. J Org Chem 83:8926-8935 |
| Condello, Carlo; Lemmin, Thomas; Stöhr, Jan et al. (2018) Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115:E782-E791 |
| Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 135:49-63 |
| Yang, Bing; Wu, Haifan; Schnier, Paul D et al. (2018) Proximity-enhanced SuFEx chemical cross-linker for specific and multitargeting cross-linking mass spectrometry. Proc Natl Acad Sci U S A 115:11162-11167 |
| Wang, Tuo; Jo, Hyunil; DeGrado, William F et al. (2017) Water Distribution, Dynamics, and Interactions with Alzheimer's ?-Amyloid Fibrils Investigated by Solid-State NMR. J Am Chem Soc 139:6242-6252 |
| Giles, Kurt; Woerman, Amanda L; Berry, David B et al. (2017) Bioassays and Inactivation of Prions. Cold Spring Harb Perspect Biol 9: |
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