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 and Marco Sardiello ()
Additional contact information
Michela Palmieri: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital
Rituraj Pal: Baylor College of Medicine
Hemanth R. Nelvagal: Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London
Parisa Lotfi: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital
Gary R. Stinnett: Baylor College of Medicine
Michelle L. Seymour: Baylor College of Medicine
Arindam Chaudhury: Dan L. Duncan Cancer Center, Baylor College of Medicine
Lakshya Bajaj: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital
Vitaliy V. Bondar: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital
Laura Bremner: Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London
Usama Saleem: Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London
Dennis Y. Tse: Cullen Eye Institute, Baylor College of Medicine
Deepthi Sanagasetti: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital
Samuel M. Wu: Cullen Eye Institute, Baylor College of Medicine
Joel R. Neilson: Dan L. Duncan Cancer Center, Baylor College of Medicine
Fred A. Pereira: Baylor College of Medicine
Robia G. Pautler: Baylor College of Medicine
George G. Rodney: Baylor College of Medicine
Jonathan D. Cooper: Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London
Marco Sardiello: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14338

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