A distinctive feature of prion protein (PrP) biogenesis, which appears central to an understanding of prion disease pathophysiology, is the observation that nascent PrP is synthesized in the form of at least three distinctive conformers that also differ in transmembrane topology. A growing body of evidence suggests that one of these, termed (Ctm)PrP, triggers a final common pathway of apoptosis occurring in response to both genetic and infectious prion disease, while another conformer, termed (Sec)PrP, is anti-apoptotic and neuroprotective. Work over the last decade has revealed a number of means by which the mix of conformers synthesized from an initially homogeneous population of nascent PrP chains can be altered. In particular, the signal sequence, and a charged region termed the Stop Transfer Effector (STE) sequence immediately preceding the transmembrane region, have been demonstrated to be sequence determinants of PrP topology. More recent data suggests that: i) other regions besides the signal sequence and STE sequence may contribute to regulation of PrP transmembrane topology and conformation, ii) interaction of distinct domains within PrP are involved in the protein's topogenesis, and iii) mapping of protein-protein interactions during translocation may provide useful information for conformer manipulation. Here we propose studies designed to i) explore new topogenic sequences and their interactions in cis, and ii) identify the partner proteins with which nascent PrP is involved in trans. We will then use this information to better understand the mechanism by which individual PrP conformers are generated, and the relationship of those mechanisms to signaling in infectious scrapie. In the long run, this work may also make possible the development of novel approaches to treatment of prion disease through conformer manipulation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG002132-26
Application #
7173814
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
26
Fiscal Year
2006
Total Cost
$209,997
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
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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