Decrease in skin prion-seeding activity of prion-infected mice treated with a compound against human and animal prions: a first possible biomarker for prion therapeutics

Authors: DING, MINGXUAN - Case Western Reserve University (CWRU); TERUYA, KENTA - Tohoku University School Of Medicine; ZHANG, WEIGUANLIU - Case Western Reserve University (CWRU); LEE, HAE WEON - Case Western Reserve University (CWRU); YUAN, JUE - Case Western Reserve University (CWRU); OGUMA, AYUMI - Tohoku University School Of Medicine; CAMACHO, MANUEL - Case Western Reserve University (CWRU); MITCHELL, MARCUS - Case Western Reserve University (CWRU); Greenlee, Justin; ZOU, WEN-QUAN - Case Western Reserve University (CWRU); KONG, QINGZHONG - Case Western Reserve University (CWRU); DOH-URA, KATSUMI - Tohoku University School Of Medicine; CUI, LI - Jilin University

Submitted to: Molecular Neurobiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/30/2021
Publication Date: 5/13/2021
Citation: Ding, M., Teruya, K., Zhang, W., Lee, H., Yuan, J., Oguma, A., Camacho, M., Mitchell, M., Greenlee, J.J., Zou, W., Kong, Q., Doh-Ura, K., Cui, L. 2021. Decrease in skin prion-seeding activity of prion-infected mice treated with a compound against human and animal prions: a first possible biomarker for prion therapeutics. Molecular Neurobiology. https://doi.org/10.1007/s12035-021-02418-6.
DOI: https://doi.org/10.1007/s12035-021-02418-6

Interpretive Summary: Prion diseases are invariably fatal neurologic diseases for which there is no known prevention or cure. Because of long incubation times and knowledge gaps in how the disease progresses, treatments are elusive. This manuscript describes the use of cellulose ethers, specifically TC-5RW, to prolong the lifespan of hamsters with prion disease. In vitro assays demonstrate that TC-5RW inhibits prion replication in skin and brain. These assays were also applied to tissues from cervids infected with chronic wasting disease (CWD) prions and humans with various prion disease confirming that these compounds inhibit prion seeding activity. These results suggest cellulose eithers may extend life after prion infection and that skin may be a useful tissue for assessing therapeutic effects of treatment compounds. Because mechanisms of neurodegeneration in prion disease are similar to other protein misfolding diseases such as Alzheimer’s disease and Parkinson’s disease, use of this assessment model could have a major impact on improving treatments for other neurodegenerative diseases.

Technical Abstract: Previous studies have revealed that the infectious scrapie isoform of prion protein (PrPSc) harbored in the skin tissue of patients or animals with prion diseases can be amplified and detected through the serial protein misfolding cyclic amplification (sPMCA) or real-time quaking-induced conversion (RT-QuIC) assays. These findings suggest that skin PrPSc-seeding activity may serve as a biomarker for diagnosis of prion diseases; however, its utility as a biomarker for prion therapeutics remains largely unknown. Cellulose ethers (CEs, such as TC-5RW), widely used as food and pharmaceutical additives, have recently been shown to prolong the lifespan of prion-infected mice and hamsters. Here we report that in transgenic (Tg) mice expressing hamster cellular prion protein (PrPC) infected with the 263K prion, prion-seeding activity becomes undetectable in the skin tissues of TC-5RW-treated Tg mice by both sPMCA and RT-QuIC assays, whereas such prion-seeding activity is readily detectable in the skin of untreated mice. Notably, TC-5RW has an inhibitory effect on the amplification of PrPSc in both skin and brain tissues by sPMCA and RT-QuIC at concentrations as low as 2 µg/mL. Moreover, we reveal that TC-5RW is able to directly decrease protease-resistant PrPSc and inhibit the seeding activity of PrPSc from chronic wasting disease and various human prion diseases. Our results suggest that the level of prion-seeding activity in the skin may serve as a useful biomarker for assessing therapeutic efficacy of compounds in clinical trial of prion diseases, and that TC-5RW may have the potential for prevention/treatment of human prion diseases.