The autophagy inducers AR‐12 and AR‐14 control prion infection
Notice bibliographique
Résumé
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 .
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».