Currently there are no known treatments that slow or prevent Alzheimer?s and other neurodegenerative diseases, and the molecular mechanisms that underlie the progression of these diseases are poorly understood. Our broad goal is to address critical problems in macromolecular structure determination of disease-relevant conformations of A? and tau prions and associated protein regulatory complexes in order to advance mechanistic understanding of prion propagation and guide novel therapeutic approaches. We will achieve this goal using high-resolution cryo-electron microscopy (cryo-EM) methods and: (1) Develop affinity capture methods on cryo-EM grids for extracting specific filaments from tissue for structure determination; (2) Determine cryo-EM structures of A? and tau fibril conformations derived from in vitro assembly and mouse models and compare with those determined from human tissue; and (3) Determine mechanisms and interactions by the Hsp70 molecular chaperone machinery that regulate prion propagation, ubiquitination, and clearance. With these goals we will identify the structural basis for amyloid fibrils that develop during disease and uncover key chaperone regulatory processes critical for quality control and clearance of proteins that form toxic amyloids.
| 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 |
| 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 |
| Watts, Joel C; Prusiner, Stanley B (2017) ?-Amyloid Prions and the Pathobiology of Alzheimer's Disease. Cold Spring Harb Perspect Med : |
| 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 |
Showing the most recent 10 out of 363 publications
