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

Nat Commun. 2017 Feb 6;8:14338. doi: 10.1038/ncomms14338.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Astrocytes
  • Autophagy / drug effects*
  • Autophagy / physiology
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Brain / cytology
  • Brain / drug effects
  • Brain / pathology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Disease Models, Animal
  • Fibroblasts
  • Gene Knockdown Techniques
  • HeLa Cells
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Transgenic
  • Molecular Chaperones / genetics
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / pathology
  • Neurons
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Phosphorylation
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Trehalose / pharmacology*
  • Trehalose / therapeutic use

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CLN3 protein, mouse
  • Heterocyclic Compounds, 3-Ring
  • MK 2206
  • Membrane Glycoproteins
  • Molecular Chaperones
  • Neuroprotective Agents
  • TFEB protein, human
  • Trehalose
  • AKT1 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt