Abstract
ABSTRACTAutophagy dysfunction is a common feature in neurodegenerative disorders characterized by accumulation of toxic protein aggregates. Increasing evidence has demonstrated that activation of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal biogenesis, can ameliorate neurotoxicity and rescue neurodegeneration in animal models. Currently known TFEB activators are mainly inhibitors of MTOR (mechanistic target of rapamycin [serine/threonine kinase]), which, as a master regulator of cell growth and metabolism, is involved in a wide range of biological functions. Thus, the identification of TFEB modulators acting without inhibiting the MTOR pathway would be preferred and probably less deleterious to cells. In this study, a synthesized curcumin derivative termed C1 is identified as a novel MTOR-independent activator of TFEB. Compound C1 specifically binds to TFEB at the N terminus and promotes TFEB nuclear translocation without inhibiting MTOR activity. By activating TFEB, C1 enhances autophagy and lysosome biogenesis in vitro and in vivo. Collectively, compound C1 is an orally effective activator of TFEB and is a potential therapeutic agent for the treatment of neurodegenerative diseases.
Highlights
IntroductionMacroautophagy ( referred to as autophagy) is a highly conserved cellular process for the bulk degradation of longlived proteins and organelles mediated by lysosomes
Macroautophagy is a highly conserved cellular process for the bulk degradation of longlived proteins and organelles mediated by lysosomes
The results indicate that curcumin analogs enhance autophagy rather than blocking lysosomal degradation
Summary
Macroautophagy ( referred to as autophagy) is a highly conserved cellular process for the bulk degradation of longlived proteins and organelles mediated by lysosomes. Curcumin is a natural polyphenolic compound derived from the herbal medicine turmeric (Curcuma longa Linn.), which is nontoxic and possesses diverse pharmacologic effects.[19] It is well documented that curcumin enhances autophagy via inhibiting the phosphoinositide 3-kinase-AKT-MTOR signaling pathway.[20,21] the poor absorption and low bioavailability of curcumin curtails its clinical application.[19,22] To improve the bioavailability and potency, a number of derivatives of curcumin have been chemically synthesized.[23,24]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
