Journal ArticleDOI
Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response.
Se Jin Jeong,Jeremiah Stitham,Trent D. Evans,Xiangyu Zhang,Astrid Rodriguez-Velez,Yu Sheng Yeh,Joan Tao,Koki Takabatake,Slava Epelman,Irfan J. Lodhi,Joel D. Schilling,Brian J. DeBosch,Abhinav Diwan,Abhinav Diwan,Babak Razani,Babak Razani +15 more
TLDR
In this article, Trehalose is shown to act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation and nuclear translocation.Abstract:
The autophagy-lysosome system is an important cellular degradation pathway that recycles dysfunctional organelles and cytotoxic protein aggregates. A decline in this system is pathogenic in many human diseases including neurodegenerative disorders, fatty liver disease, and atherosclerosis. Thus there is intense interest in discovering therapeutics aimed at stimulating the autophagy-lysosome system. Trehalose is a natural disaccharide composed of two glucose molecules linked by a ɑ-1,1-glycosidic bond with the unique ability to induce cellular macroautophagy/autophagy and with reported efficacy on mitigating several diseases where autophagy is dysfunctional. Interestingly, the mechanism by which trehalose induces autophagy is unknown. One suggested mechanism is its ability to activate TFEB (transcription factor EB), the master transcriptional regulator of autophagy-lysosomal biogenesis. Here we describe a potential mechanism involving direct trehalose action on the lysosome. We find trehalose is endocytically taken up by cells and accumulates within the endolysosomal system. This leads to a low-grade lysosomal stress with mild elevation of lysosomal pH, which acts as a potent stimulus for TFEB activation and nuclear translocation. This process appears to involve inactivation of MTORC1, a known negative regulator of TFEB which is sensitive to perturbations in lysosomal pH. Taken together, our data show the trehalose can act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation. Our work not only sheds light on trehalose action but suggests that mild alternation of lysosomal pH can be a novel method of inducing the autophagy-lysosome system.Abbreviations: ASO: antisense oligonucleotide; AU: arbitrary units; BMDM: bone marrow-derived macrophages; CLFs: crude lysosomal fractions; CTSD: cathepsin D; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; MAP1LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTORC1: mechanistic target of rapamycin kinase complex 1; pMAC: peritoneal macrophages; SLC2A8/GLUT8: solute carrier family 2, (facilitated glucose transporter), member 8; TFEB: transcription factor EB; TMR: tetramethylrhodamine; TREH: trehalase.read more
Citations
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Journal ArticleDOI
Loss of endosomal exchanger NHE6 leads to pathological changes in tau in human neurons
Marty A. Fernandez,Fatmata Isha Bah,Li Ma,YouJin Lee,Michael Schmidt,Elizabeth Welch,Eric M. Morrow,Tracy L. Young-Pearse +7 more
TL;DR: In this article , the authors demonstrate that NHE6 knockout leads to lysosomal and autophagy dysfunction involving reduced lyssomal number and protease activity, diminished autophagic flux, and p62 accumulation.
Journal ArticleDOI
Trehalose Activates Hepatic and Myocardial Autophagy and Has Anti-Inflammatory Effects in db/db Diabetic Mice
T. A. Korolenko,M. V. Ovsyukova,N. P. Bgatova,Igor D. Ivanov,S. I. Makarova,Valentin A. Vavilin,A. Popov,E. I. Yuzhik,E. V. Koldysheva,Erik C. Korolenko,E. L. Zavjalov,Tamara G. Amstislavskaya +11 more
TL;DR: The autophagyactivation by trehalose had several positive effects on the heart and liver of db/db mice; therefore, lipophagy activation seems to be a promising therapy for diabetes.
Journal ArticleDOI
Trehalose Reduces Nerve Injury Induced Nociception in Mice but Negatively Affects Alertness.
Vanessa Kraft,Katja Schmitz,Annett Wilken-Schmitz,Annett Wilken-Schmitz,Gerd Geisslinger,Gerd Geisslinger,Marco Sisignano,Marco Sisignano,Irmgard Tegeder +8 more
TL;DR: In this paper, the effects of continuous trehalose administration via drinking water using the mouse Spared Nerve Injury model of neuropathic pain were assessed. Trehalose had no effect on drinking, feeding, voluntary wheel running, motor coordination, locomotion, and open field, elevated plus maze, and Barnes maze behavior, showing that it was well tolerated.
Journal ArticleDOI
Potential therapeutic effects of natural compounds targeting autophagy to alleviate podocyte injury in glomerular diseases.
Tongtong Liu,Qi-hua Jin,Fei-Hong Ren,Liping Yang,Hui-Min Mao,Fang Ma,Yuyang Wang,Ping Li,Yongli Zhan +8 more
TL;DR: In this paper , the authors reviewed the use of natural compounds and their derivatives as autophagy regulators and discussed their potential applications in ameliorating podocyte injury and their medical uses.
Journal ArticleDOI
Trehalose Suppresses Lysosomal Anomalies in Supporting Cells of Oocytes and Maintains Female Fertility
Woojin Kang,Eri Ishida,Mitsuyoshi Amita,Kuniko Tatsumi,Hitomi Yonezawa,Miku Yohtsu,Daiki Katano,Kae Onozawa,Erika Kaneko,Wakako Iwasaki,Natsuko Naito,Mitsutoshi Yamada,Natsuko Kawano,Mami Miyado,Ban Sato,Hidekazu Saito,Takakazu Saito,Kenji Miyado +17 more
TL;DR: It is suggested that autophagy maintains the healthy state of the supporting cells of human oocytes by suppressing the formation of lysosomes, which provides insights into the therapeutic effects of trehalose on female fertility.
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