Abstract

ABSTRACTPrion diseases are fatal transmissible neurodegenerative disorders that affect animals and humans. Prions are proteinaceous infectious particles consisting of a misfolded isoform of the cellular prion protein PrPC, termed PrPSc. PrPSc accumulates in infected neurons due to partial resistance to proteolytic digestion. Using compounds that interfere with the production of PrPSc or enhance its degradation cure prion infection in vitro, but most drugs failed when used to treat prion-infected rodents. In order to synergize the effect of anti-prion drugs, we combined drugs interfering with the generation of PrPSc with compounds inducing PrPSc degradation. Here, we tested autophagy stimulators (rapamycin or AR12) and cellulose ether compounds (TC-5RW or 60SH-50) either as single or combination treatment of mice infected with RML prions. Single drug treatments significantly extended the survival compared to the untreated group. As anticipated, also all the combination therapy groups showed extended survival compared to the untreated group, but no combination treatment showed superior effects to 60SH-50 or TC-5RW treatment alone. Unexpectedly, we later found that combining autophagy stimulator and cellulose ether treatment in cultured neuronal cells mitigated the pro-autophagic activity of AR12 and rapamycin, which can in part explain the in vivo results. Overall, we show that it is critical to exclude antagonizing drug effects when attempting combination therapy. In addition, we identified AR-12 as a pro-autophagic drug that significantly extends survival of prion-infected mice, has no adverse side effects on the animals used in this study, and can be useful in future studies.

Highlights

  • Prion diseases are neurodegenerative disorders in humans and animals that are invariably fatal

  • Treatment with autophagy stimulators AR12 or rapamycin significantly prolonged the survival of RML infected mice

  • We examined the effect of treatment with the autophagy inducer AR12 on the survival times of FVB mice infected intra-cerebrally with RML prions

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Summary

Introduction

Prion diseases are neurodegenerative disorders in humans and animals that are invariably fatal. Human prion diseases occur in sporadic, genetic, and acquired forms. The human forms of prion disease include familial, sporadic, iatrogenic and variant Creutzfeldt-Jakob disease (CJD), GerstmannSträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). Animal forms are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle and other species, and chronic wasting disease (CWD) in deer, reindeer, elk and moose [3,4,5,6,7]. Vacuolation, astrogliosis and microglial activation is the major histopathological findings in prion disease. This results in spongiform degeneration of the central nervous system (CNS), leading to ataxia, behavioural changes and highly progressive loss of intellectual propensity [8,9]

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