Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/66104
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
Publisher: Nature Publishing Group
Source: Nature communications, 2017, v. 8, 14338 How to cite?
Journal: Nature communications 
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.
URI: http://hdl.handle.net/10397/66104
EISSN: 2041-1723
DOI: 10.1038/ncomms14338
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