Quinacrine promotes replication and conformational mutation of chronic wasting disease prions
Quinacrine promotes replication and conformational mutation of chronic
wasting disease prions
Jifeng Bian, Hae-Eun Kang, and Glenn C. Telling1 Author Affiliations
Prion Research Center and Department of Microbiology, Immunology and
Pathology, Colorado State University, Fort Collins, CO 80523 Edited by Charles
Weissmann, The Scripps Research Institute, Jupiter, Florida, and approved March
6, 2014 (received for review November 30, 2013)
Abstract Authors & Info Metrics PDF Significance Searching for drugs to
prevent conversion of host-encoded prion protein (PrPC) to its infectious
conformation (PrPSc) is a key strategy in the pursuit of therapies for prion
disorders: fatal, transmissible epidemic diseases of unpredictable occurrence
and uncertain zoonotic potential. Despite quinacrine’s ability to reduce mouse
PrPSc in cell models, its use to treat patients has been unsuccessful. Here, we
show that quinacrine augments PrPSc and intensifies replication of prions,
causing chronic wasting disease of deer, elk, and moose, and that the resulting
prions have altered conformational and transmission properties. Our finding,
that a drug capable of restraining PrPSc in one species acts to improve
replicative ability and induce mutation in another, forces reexamination of
current strategies to combat these diseases.
Abstract Quinacrine’s ability to reduce levels of pathogenic prion protein
(PrPSc) in mouse cells infected with experimentally adapted prions led to
several unsuccessful clinical studies in patients with prion diseases, a 10-y
investment to understand its mechanism of action, and the production of related
compounds with expectations of greater efficacy. We show here, in stark contrast
to this reported inhibitory effect, that quinacrine enhances deer and elk PrPSc
accumulation and promotes propagation of prions causing chronic wasting disease
(CWD), a fatal, transmissible, neurodegenerative disorder of cervids of
uncertain zoonotic potential. Surprisingly, despite increased prion titers in
quinacrine-treated cells, transmission of the resulting prions produced
prolonged incubation times and altered PrPSc deposition patterns in the brains
of diseased transgenic mice. This unexpected outcome is consistent with
quinacrine affecting the intrinsic properties of the CWD prion. Accordingly,
quinacrine-treated CWD prions were comprised of an altered PrPSc conformation.
Our findings provide convincing evidence for drug-induced conformational
mutation of prions without the prerequisite of generating drug-resistant
variants of the original strain. More specifically, they show that a drug
capable of restraining prions in one species/strain setting, and consequently
used to treat human prion diseases, improves replicative ability in another and
therefore force reconsideration of current strategies to screen antiprion
compounds.
Friday, October 11, 2013 Quinacrine treatment trial for sporadic
Creutzfeldt-Jakob disease Article http://creutzfeldt-jakob-disease.blogspot.com/2013/10/quinacrine-treatment-trial-for-sporadic.html
Tuesday, June 14, 2011
sporadic CJD, Quinacrine Study, MRI misdiagnosis USA
Tuesday, June 14, 2011
Clinical research in CJD at a U.S. clinical prion research center: CJD
Quinacrine Study results and improved diagnosis of prion disease
Thursday, October 15, 2009
ANA: No Benefit for Quinacrine in CJD
TSS
posted by Terry S. Singeltary Sr. at
10:34 AM
0 Comments:
Post a Comment
Subscribe to Post Comments [Atom]
<< Home