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Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential.
- Source :
-
Nature communications [Nat Commun] 2015 Oct 27; Vol. 6, pp. 8620. Date of Electronic Publication: 2015 Oct 27. - Publication Year :
- 2015
-
Abstract
- Autophagy is a conserved homeostatic process active in all human cells and affecting a spectrum of diseases. Here we use a pharmaceutical screen to discover new mechanisms for activation of autophagy. We identify a subset of pharmaceuticals inducing autophagic flux with effects in diverse cellular systems modelling specific stages of several human diseases such as HIV transmission and hyperphosphorylated tau accumulation in Alzheimer's disease. One drug, flubendazole, is a potent inducer of autophagy initiation and flux by affecting acetylated and dynamic microtubules in a reciprocal way. Disruption of dynamic microtubules by flubendazole results in mTOR deactivation and dissociation from lysosomes leading to TFEB (transcription factor EB) nuclear translocation and activation of autophagy. By inducing microtubule acetylation, flubendazole activates JNK1 leading to Bcl-2 phosphorylation, causing release of Beclin1 from Bcl-2-Beclin1 complexes for autophagy induction, thus uncovering a new approach to inducing autophagic flux that may be applicable in disease treatment.
- Subjects :
- Acetylation drug effects
Alzheimer Disease drug therapy
Alzheimer Disease metabolism
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism
Humans
Lysosomes drug effects
Lysosomes metabolism
Mebendazole analogs & derivatives
Mebendazole pharmacology
Microtubules drug effects
Microtubules metabolism
Alzheimer Disease physiopathology
Autophagy drug effects
Drug Evaluation, Preclinical
Small Molecule Libraries pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 26503418
- Full Text :
- https://doi.org/10.1038/ncomms9620