TY - JOUR
T1 - Cellulose ether treatment in vivo generates chronic wasting disease prions with reduced protease resistance and delayed disease progression
AU - Hannaoui, Samia
AU - Arifin, Maria Immaculata
AU - Chang, Sheng Chun
AU - Yu, Jie
AU - Gopalakrishnan, Preetha
AU - Doh-ura, Katsumi
AU - Schatzl, Hermann M.
AU - Gilch, Sabine
N1 - Funding Information:
We are grateful to the Alberta Prion Research Institute (grants OPS002 to HMS, PEX17008 to SG, HMS and KD-u) and the Natural Science and Engineering Research Council for funding. SG is supported by the Canada Research Chairs program. We thank Lilian Oribhabor and Bukola Alli for taking excellent care of the mice used in this study. We also thank the animal facility staff of CCCMG, University of Calgary for excellent animal care. The authors have no conflict of interest. All experiments were conducted in compliance with the ARRIVE guidelines.
Publisher Copyright:
© 2019 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Chronic wasting disease (CWD) is a prion disease of free-ranging and farmed cervids that is highly contagious because of extensive prion shedding and prion persistence in the environment. Previously, cellulose ether compounds (CEs) have been shown to significantly extend the survival of mice inoculated with mouse-adapted prion strains. In this study, we used CEs, TC-5RW, and 60SH-50, in vitro and in vivo to assess their efficacy to interfere with CWD prion propagation. In vitro, CEs inhibited CWD prion amplification in a dose-dependent manner. Transgenic mice over-expressing elk PrPC (tgElk) were injected subcutaneously with a single dose of either of the CEs, followed by intracerebral inoculation with different CWD isolates from white tailed deer, mule deer, or elk. All treated groups showed a prolonged survival of up to more than 30 % when compared to the control group regardless of the CWD isolate used for infection. The extended survival in the treated groups correlated with reduced proteinase K resistance of prions. Remarkably, passage of brain homogenates from treated or untreated animals in tgElk mice resulted in a prolonged life span of mice inoculated with homogenates from CE-treated mice (of + 17%) even in the absence of further treatment. Besides the delayed disease onset upon passage in TgElk mice, the reduced proteinase K resistance was maintained but less pronounced. Therefore, these compounds can be very useful in limiting the spread of CWD in captive and wild-ranging cervids. (Figure presented.).
AB - Chronic wasting disease (CWD) is a prion disease of free-ranging and farmed cervids that is highly contagious because of extensive prion shedding and prion persistence in the environment. Previously, cellulose ether compounds (CEs) have been shown to significantly extend the survival of mice inoculated with mouse-adapted prion strains. In this study, we used CEs, TC-5RW, and 60SH-50, in vitro and in vivo to assess their efficacy to interfere with CWD prion propagation. In vitro, CEs inhibited CWD prion amplification in a dose-dependent manner. Transgenic mice over-expressing elk PrPC (tgElk) were injected subcutaneously with a single dose of either of the CEs, followed by intracerebral inoculation with different CWD isolates from white tailed deer, mule deer, or elk. All treated groups showed a prolonged survival of up to more than 30 % when compared to the control group regardless of the CWD isolate used for infection. The extended survival in the treated groups correlated with reduced proteinase K resistance of prions. Remarkably, passage of brain homogenates from treated or untreated animals in tgElk mice resulted in a prolonged life span of mice inoculated with homogenates from CE-treated mice (of + 17%) even in the absence of further treatment. Besides the delayed disease onset upon passage in TgElk mice, the reduced proteinase K resistance was maintained but less pronounced. Therefore, these compounds can be very useful in limiting the spread of CWD in captive and wild-ranging cervids. (Figure presented.).
KW - PrP conformation
KW - cellulose ether
KW - chronic wasting disease
KW - prions
KW - prophylactic
KW - therapeutic
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U2 - 10.1111/jnc.14877
DO - 10.1111/jnc.14877
M3 - Article
C2 - 31553058
AN - SCOPUS:85074084228
VL - 152
SP - 727
EP - 740
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 6
ER -