The autophagy inducers AR‐12 and AR‐14 control prion infection
Bibliographic record
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 PrP Sc 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 Information This 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 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".