MTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases

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

doi:10.1038/ncomms14338

MTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases

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

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330 Scopus citations

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.

Original language	English
Article number	14338
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14338
State	Published - Feb 6 2017

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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. (2017). MTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases. Nature communications, 8, Article 14338. https://doi.org/10.1038/ncomms14338

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title = "MTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases",

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.",

author = "Michela Palmieri and Rituraj Pal and Nelvagal, {Hemanth R.} and Parisa Lotfi and Stinnett, {Gary R.} and Seymour, {Michelle L.} and Arindam Chaudhury and Lakshya Bajaj and Bondar, {Vitaliy V.} and Laura Bremner and Usama Saleem and Tse, {Dennis Y.} and Deepthi Sanagasetti and Wu, {Samuel M.} and Neilson, {Joel R.} and Pereira, {Fred A.} and Pautler, {Robia G.} and Rodney, {George G.} and Cooper, {Jonathan D.} and Marco Sardiello",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = feb,

day = "6",

doi = "10.1038/ncomms14338",

language = "English",

volume = "8",

journal = "Nature communications",

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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 2017, 'MTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases', Nature communications, vol. 8, 14338. https://doi.org/10.1038/ncomms14338

TY - JOUR

T1 - MTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases

AU - Palmieri, Michela

AU - Pal, Rituraj

AU - Nelvagal, Hemanth R.

AU - Lotfi, Parisa

AU - Stinnett, Gary R.

AU - Seymour, Michelle L.

AU - Chaudhury, Arindam

AU - Bajaj, Lakshya

AU - Bondar, Vitaliy V.

AU - Bremner, Laura

AU - Saleem, Usama

AU - Tse, Dennis Y.

AU - Sanagasetti, Deepthi

AU - Wu, Samuel M.

AU - Neilson, Joel R.

AU - Pereira, Fred A.

AU - Pautler, Robia G.

AU - Rodney, George G.

AU - Cooper, Jonathan D.

AU - Sardiello, Marco

PY - 2017/2/6

Y1 - 2017/2/6

N2 - 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.

AB - 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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U2 - 10.1038/ncomms14338

DO - 10.1038/ncomms14338

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AN - SCOPUS:85011898443

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

M1 - 14338

ER -

MTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases

Abstract

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