Tuesday, April 08, 2014

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






Post a Comment

Subscribe to Post Comments [Atom]

<< Home