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

Mingxuan Ding,Qingzhong Kong,Katsumi Doh-Ura,Manuel V Camacho,Li Cui,Hae Weon Lee,Justin J Greenlee,Jue Yuan,Kenta Teruya,Weiguanliu Zhang,Wen-Quan Zou,Aaron Foutz,Ayumi Oguma,Marcus Mitchell

doi:10.1007/s12035-021-02418-6

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 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 (PrPC) 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 PrPSc in both skin and brain tissues by sPMCA and RT-QuIC. 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 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.

Highlights

Prion diseases or transmissible spongiform encephalopathies are a group of neurodegenerative diseases affecting the central nervous system of humans and animals, including Creutzfeldt-Jakob disease (CJD), kuru, fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and variably protease-sensitive prionopathy (VPSPr) in humans, and scrapie in sheep and goats, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) in elk and deer [1]
To determine whether a potential therapeutic effect could be reflected in the prion-seeding activity of skin tissues of infected animals treated with the compound, we intracerebrally inoculated hemizygous Tg7 mice with the 263 K prions
We further investigated the effect of TC-5RW on the seeding activity of P rPSc from various human prion diseases including sCJDMM1, sCJDMM2, sCJDMV2, sCJDVV2, fCJDE200K, FFI, and fCJDV180I by realtime quaking-induced conversion (RT-QuIC) assay (Fig. 6A through G)

Summary

Introduction

Prion diseases or transmissible spongiform encephalopathies are a group of neurodegenerative diseases affecting the central nervous system of humans and animals, including Creutzfeldt-Jakob disease (CJD), kuru, fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and variably protease-sensitive prionopathy (VPSPr) in humans, and scrapie in sheep and goats, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) in elk and deer [1] They have a long incubation period and a 100% fatality rate. In animal models including 263 K scrapie prion-infected hamsters and sporadic CJD (sCJD) prion-infected humanized transgenic (Tg) mice expressing human wild-type PrP, we further observed that skin P rPSc was detectable by realtime quaking-induced conversion (RT-QuIC) and serial protein misfolding cyclic amplification (sPMCA) assays long before clinical signs and brain lesions manifested [5] These observations provide the proof-of-concept that skin PrPSc may be a biomarker for early preclinical diagnosis of prion diseases. It is unclear whether the level of prion-seeding activity in the skin can serve as a biomarker for assessing the efficacy of anti-prion therapeutics

Methods

Results

Conclusion