Prion diseases are diseases of protein conformation which arise through the abnormal metabolism of the cellular prion protein (PrPc). We currently lack a detailed understanding the molecular level, of he mechanism by which the aberrant forms of PrP are derived from PrPc. Our approach has been to generate large and diverse panels of recombinant monoclonal antibodies to PrP by immunizing PrP-knockout mice with different PrP antigenic preparations and rescuing antibodies via phage display libraries. These novel antibodies have subsequently been employed as sensitive probes to generate a structural map of PrP conformation transition. To date, the antibodies have, together with protein engineering, structural and spectroscopic studies of PrP, begun to provide the first glimpses of conformation rearrangements involved in the acquisition of prion infectivity. Here, in pursuit of our ongoing goal to define events in the genesis of abnormal PrP isoforms, we propose to use antibodies to map the conformations of oligomeric forms of PrP since these oligomers likely form a structural link between PrPc and PrPSc. We will generate novel antibodies against oligomeric forms of PrP refolded to adopt both alpha-helical and beta-sheet conformations. We also aim to generate antibodies specifically recognizing unpurified oligomeric PrPSc as it occurs in infected tissues. Collectively this conformational information will be employed to identify key structural changes taking place as PrPSc is formed from PrPc. In addition, we propose to generate antibodies to the octapeptide repeat region of PrP, to examine conformational changes ensuing from the binding of copper-II-ions and to facilitate immunoaffinity purification of PrP106 and its derivatives.
| 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 |
| Johnson, Noah R; Condello, Carlo; Guan, Shenheng et al. (2017) Evidence for sortilin modulating regional accumulation of human tau prions in transgenic mice. Proc Natl Acad Sci U S A 114:E11029-E11036 |
| 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 |
Showing the most recent 10 out of 363 publications
