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mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases

Palmieri, Michela, Pal, Rituraj, Nelvagal, Hemanth R., Lotfi, Parisa, Stinnett, Gary R., Seymour, Michelle L., Chaudhury, Arindam, Bajaj, Lakshya, Bondar, Vitaliy V., Bremner, Laura, Saleem, Usama, Tse, Dennis Y., Sanagasetti, Deepthi, Wu, Samuel M., Neilson, Joel R., Pereira, Fred A., Pautler, Robia G., Rodney, George G., Cooper, Jonathan D., Sardiello, Marco·2017·Nature Communications
DOI 10.1038/ncomms14338PMC PMC5303831
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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.

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Metadata

Authors
Palmieri, M., Pal, R., Nelvagal, H. R., Lotfi, P., Stinnett, G. R., Seymour, M. L., Chaudhury, A., Bajaj, L., Bondar, V. V., Bremner, L., Saleem, U., Tse, D. Y., Sanagasetti, D., Wu, S. M., Neilson, J. R., Pereira, F. A., Pautler, R. G., Rodney, G. G., Cooper, J. D., & Sardiello, M.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-02-06
Volume
8
Issue
1
ISSN
2041-1723
DOI
10.1038/ncomms14338
PMC
PMC5303831
Cited by
383
References
11
Language
en
Update notices
correction (2017-06-13)
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