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

• Published in: Molecular neurobiology 2021-09, Vol.58 (9), p.4280-4292
• Main Authors: Ding, Mingxuan, Teruya, Kenta, Zhang, Weiguanliu, Lee, Hae Weon, Yuan, Jue, Oguma, Ayumi, Foutz, Aaron, Camacho, Manuel V., Mitchell, Marcus, Greenlee, Justin J., Kong, Qingzhong, Doh-ura, Katsumi, Cui, Li, Zou, Wen-Quan
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Brain - pathology; Cell Biology; Cellulose; Chronic wasting disease; Ethers; Food additives; Life span; Mice; Mice, Transgenic; Neurobiology; Neurology; Neurosciences; Prion Diseases - metabolism; Prion Diseases - pathology; Prion protein; Protein folding; Proteins; PrPSc Proteins - metabolism; Scrapie; Skin - metabolism; Transgenic mice; Transmissible spongiform encephalopathy
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-021-02418-6

Previous studies have revealed that the infectious scrapie isoform of prion protein (PrP Sc ) 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 PrP Sc -seeding activity may serve as a biomarker for the 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 (PrP C ) infected with the 263K prion, the 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 exhibits an inhibitory effect on the in vitro amplification of PrP Sc in both skin and brain tissues by sPMCA and RT-QuIC. Moreover, we reveal that TC-5RW is able to directly decrease protease-resistant PrP Sc and inhibit the seeding activity of PrP Sc 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 the therapeutic efficacy of compounds in a clinical trial of prion diseases and that TC-5RW may have the potential for the prevention/treatment of human prion diseases.