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Title: | MTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases | Authors: | Palmieri, M Pal, R Nelvagal, HR Lotfi, P Stinnett, GR Seymour, ML Chaudhury, A Bajaj, L Bondar, VV Bremner, L Saleem, U Tse, DY Sanagasetti, D Wu, SM Neilson, JR Pereira, FA Pautler, RG Rodney, GG Cooper, JD Sardiello, M |
Issue Date: | 2017 | Source: | Nature communications, 6 2017, v. 8, no. , 14338, p. 1-16 | Abstract: | Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases. | Publisher: | Nature Publishing Group | Journal: | Nature communications | EISSN: | 2041-1723 | DOI: | 10.1038/ncomms14338 | Rights: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ © The Author(s) 2017 The following publication Palmieri, M., Pal, R., Nelvagal, H. et al. mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases. Nat Commun 8, 14338 (2017) is available at https://dx.doi.org/10.1038/ncomms14338 |
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