Assessment of the PrPc amino-terminal domain in prion species barriers
Assessment of the PrPc amino-terminal domain in prion species barriers
Kristen A. Davenporta, Davin M. Hendersona, Candace K. Mathiasona and
Edward A. Hoovera# + Author Affiliations
Prion Research Center, Department of Microbiology, Immunology and
Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado
State University, Fort Collins, CO 80523a ABSTRACT Chronic wasting disease (CWD)
in cervids and bovine spongiform encephalopathy (BSE) in cattle are prion
diseases that are caused by the same protein-misfolding mechanism, but appear to
pose different risks to humans. We are interested in understanding the
differences between the species barriers of CWD and BSE. We used real-time,
quaking-induced conversion (RT-QuIC) to model the central molecular event in
prion disease, the templated misfolding of the normal prion protein, PrPc, to a
pathogenic, amyloid isoform, PrPSc. We examined the role of the PrPc
amino-terminal domain (NTD, aa23-90) in cross-species conversion by comparing
the conversion efficiency of various prion seeds in either full-length
(aa23-231) or truncated (aa90-231) PrPc. We demonstrate that the presence of
white-tailed deer and bovine NTDs hindered seeded conversion of PrPc, but human
and bank vole NTDs did the opposite. Additionally, full-length human and bank
vole PrPc were more likely to be converted to amyloid by CWD prions than were
their truncated forms. A chimera with replacement of the human NTD by the bovine
NTD resembled human PrPc. The requirement for an NTD, but not for the specific
human sequence, suggests that the NTD interacts with other regions of the human
PrPc to increase promiscuity. These data contribute to the evidence that, in
addition to primary sequence, prion species barriers are controlled by
interactions of the substrate NTD with the rest of the substrate PrPc molecule.
Importance We demonstrate that the amino-terminal domain of the normal
prion protein, PrPc, hinders seeded conversion of bovine and white-tailed deer
PrPc to the prion form, but it facilitates conversion of the human and bank vole
PrPc to the prion form. Additionally, we demonstrate that the amino-terminal
domain of human and bank vole PrPc requires interaction with the rest of the
molecule to facilitate conversion by CWD prions. These data suggest that
interactions of the amino-terminal domain with the rest of the PrPc molecule
play an important role in the susceptibility of humans to CWD prions.
snip...
We found that human rPrPc can be readily converted to an amyloid state by
CWD prions, and that the NTD facilitates this conversion. As there is little
evidence for the susceptibility of humans to CWD, the biologic significance of
our observation remains to be determined. However, the role of the NTD in this
in vitro phenomenon may be important to the in vivo mechanism as well. RT-QuIC,
transgenic mouse bioassay, and PMCA measure different outcomes. This manuscript
compares the efficiency of initial amyloid formation, while bioassay and PMCA
reflect total accumulation of protease-resistant PrPSc, which may explain the
difference in the apparent susceptibility of full-length human rPrPc in these
models. The molecular underpinnings for species barriers and trans-species prion
conversion remain a complex, yet important problem in prion biology. We propose
that an interaction between the amino terminal
FOOTNOTES
↵#Address correspondence to Edward A. Hoover, edward.hoover@colostate.edu
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
‘’We demonstrate that the presence of white-tailed deer and bovine NTDs
hindered seeded conversion of PrPc, but human and bank vole NTDs did the
opposite. Additionally, full-length human and bank vole PrPc were more likely to
be converted to amyloid by CWD prions than were their truncated forms. ‘’
***Moreover, sporadic disease has never been observed in breeding colonies
or primate research laboratories, most notably among hundreds of animals over
several decades of study at the National Institutes of Health25, and in nearly
twenty older animals continuously housed in our own facility.***
Monday, May 02, 2016
*** Zoonotic Potential of CWD Prions: An Update Prion 2016 Tokyo ***
SCRAPIE AND CWD ZOONOSIS
PRION 2016 CONFERENCE TOKYO
Saturday, April 23, 2016
*** SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016
***
Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X
TSS
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