The autophagy inducers AR‐12 and AR‐14 control prion infection

Abstract

Prion diseases are fatal infectious neurodegenerative disorders that affect both man and animals. The autocatalytic conversion of the cellular prion protein (PrPC) into the pathologic isoform PrPSc is a key feature in prion pathogenesis. Loss of neurons, astrogliosis and mild microglia activation are the main pathological features of prion diseases. This results in a progressive spongiform degeneration of the central nervous system, leading to ataxia, behavioral changes and, in humans, highly progressive loss of intellectual abilities. In the last two decades, great efforts have been made to establish treatment options for prion diseases. These included testing existing drugs for anti‐prion activity in experimental models with only a few agents progressing to human studies of patients with prion diseases. Investigations to date have not resulted in a recognized/proven treatment for prion diseases. AR‐12 is an IND‐approved derivative of celecoxib that demonstrated preclinical activity against several microbial diseases. Recently, AR‐12 has been shown to enhance clearance of misfolded proteins through autophagy stimulation. The latter proposes AR‐12 to be a potential therapeutic agent for neurodegenerative disorders. In the present study, we evaluated the role of AR‐12 and its derivatives in controlling prion infection. We tested AR‐12 in prion infected neuronal and non‐neuronal cell lines. Immunoblotting and confocal microscopy results showed that AR‐12 and its analogue AR‐14 reduced PrPSc levels after only 72 hours of treatment. Furthermore, infected cells were cured of PrPSc after exposure of AR‐12 or AR‐14 for only two weeks. We partially attribute the influence of the AR compounds on prion propagation to autophagy stimulation. Currently, we are investigating the effect of AR‐compounds in vivo. We are also evaluating the effect of combining AR‐ compounds with other anti‐prion agents to investigate the effect on PrPSc and prion seeding activity. Taken together, this study demonstrates that AR‐12 and the AR‐14 analogue are potential new therapeutic agents for prion diseases and possibly protein misfolding disorders involving prion‐like mechanisms.Support or Funding InformationThis work was supported by grants from the Alberta Prion Research Institute (201200002), the National Institute of Health (R01 NS076853‐01A1), the Canada Foundation for Innovation (Leaders Opportunity Fund project #32212) and was performed within the framework of the Calgary Prion Research Unit (CPRU; APRI grant 201600010). B.A.A. is an Alberta Innovates Health Solutions postgraduate fellow, D. A. is an Eyes High postgraduate fellow. S. T. is an Eyes High and Killam PhD student. S.G. is supported by the Canada Research Chair program. There are no conflicts of interest. There was no financial support from ARNO Therapeutics for performing this study. U.S. Patent Application entitled “COMPOSITIONS AND METHODS FOR REDUCING PRION LEVELS” filed February 28, 2017 as 15/445,964; VLP Ref: 2242‐00‐018U01.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.