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

Author

Listed:
  • 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
    School of Optometry, The Hong Kong Polytechnic University)

  • 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
    Cardiovascular Research Institute, 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)

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.

Suggested Citation

  • 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 & De, 2017. "mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases," Nature Communications, Nature, vol. 8(1), pages 1-19, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14338
    DOI: 10.1038/ncomms14338
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    Cited by:

    1. David Matye & Sumedha Gunewardena & Jianglei Chen & Huaiwen Wang & Yifeng Wang & Mohammad Nazmul Hasan & Lijie Gu & Yung Dai Clayton & Yanhong Du & Cheng Chen & Jacob E. Friedman & Shelly C. Lu & Wen-, 2022. "TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Xinran Li & Cong Xiang & Shilei Zhu & Jiansheng Guo & Chang Liu & Ailian Wang & Jin Cao & Yan Lu & Dante Neculai & Pinglong Xu & Xin-Hua Feng, 2024. "SNX8 enables lysosome reformation and reverses lysosomal storage disorder," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Sayan Ghosh & Ruchi Sharma & Sridhar Bammidi & Victoria Koontz & Mihir Nemani & Meysam Yazdankhah & Katarzyna M. Kedziora & Donna Beer Stolz & Callen T. Wallace & Cheng Yu-Wei & Jonathan Franks & Devi, 2024. "The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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