Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential

• DOI: 10.1038/ncomms9620
• Publication Date: 2015-10-27T10:17:06Z
• Authors: Santosh Chauhan; Zahra Ahmed; Steven B. Bradfute; John Arko-Mensah; Michael A. Mandell; Seong Won Choi; Tomonori Kimura; Fabien Blanchet; Anna Waller; Michal H. Mudd; Shanya Jiang; Larry Sklar; Graham S. Timmins; Nicole Maphis; Kiran Bhaskar; Vincent Piguet; Vojo Deretic
• Keywords: TFEB

Abstract Autophagy is a conserved homeostatic process active in all human cells and affecting spectrum of diseases. Here we use pharmaceutical screen to discover new mechanisms for activation autophagy. We identify subset pharmaceuticals inducing autophagic flux with effects diverse cellular systems modelling specific stages several diseases such as HIV transmission hyperphosphorylated tau accumulation Alzheimer’s disease. One drug, flubendazole, potent inducer autophagy initiation by acetylated dynamic microtubules reciprocal way. Disruption flubendazole results mTOR deactivation dissociation from lysosomes leading TFEB (transcription factor EB) nuclear translocation By microtubule acetylation, activates JNK1 Bcl-2 phosphorylation, causing release Beclin1 Bcl-2-Beclin1 complexes induction, thus uncovering approach that may be applicable disease treatment.