Cellulose ether treatment in vivo generates chronic wasting disease prions with reduced protease resistance and delayed disease progression. Issue 6 (16th October 2019)

• Record Type: Journal Article
• Authors: Hannaoui, Samia; Arifin, Maria Immaculata; Chang, Sheng Chun; Yu, Jie; Gopalakrishnan, Preetha; Doh‐ura, Katsumi; Schatzl, Hermann M.; Gilch, Sabine
• Is Part Of: Journal of neurochemistry. Volume 152:Issue 6(2020)
• Page Start: 727
• Page End: 740
• Publication Date: 2019-10-16
• Subjects: cellulose ether -- chronic wasting disease -- prions -- prophylactic -- PrPSc conformation -- therapeutic; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14877
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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 PrP C (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. Abstract : Chronic wasting disease (CWD) is a prion disease affecting free‐ranging and farmed cervids, with substantial lateral transmission and effective shedding, making its containment nearly impossible. This poses a significant concern for public health, economy and ecology. Here we demonstrate that cellulose ether (CE) treatment of CWD infected transgenic mice (TgElk) prolongs survival and modifies the biochemical and biological properties of prions, resulting in reduced protease resistance along with delayed clinical disease. Therefore, CE treatment could be a good strategy to reduce CWD spreading, limiting its potential of transmission to cerid and non‐cervid animals and potentially to humans.