mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases.
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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.
Michela
M
Palmieri
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Rituraj
R
Pal
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London SE5 9RT, UK.
Hemanth R
HR
Nelvagal
Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.
Parisa
P
Lotfi
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Gary R
GR
Stinnett
Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Michelle L
ML
Seymour
Department of Molecular Physiology and Biophysics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Arindam
A
Chaudhury
Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.
Lakshya
L
Bajaj
Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.
Vitaliy V
VV
Bondar
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London SE5 9RT, UK.
Laura
L
Bremner
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London SE5 9RT, UK.
Usama
U
Saleem
Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.|School of Optometry, The Hong Kong Polytechnic University, Kowloon, Hong Kong.
Dennis Y
DY
Tse
Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.
Deepthi
D
Sanagasetti
Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
Samuel M
SM
Wu
Department of Molecular Physiology and Biophysics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Joel R
JR
Neilson
Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Fred A
FA
Pereira
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Robia G
RG
Pautler
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
George G
GG
Rodney
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London SE5 9RT, UK.
Jonathan D
JD
Cooper
Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.
Marco
M
Sardiello
D000818:Animals; D001253:Astrocytes; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009474:Neurons; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014199:Trehalose / Q000494:pharmacology* / Q000627:therapeutic use
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C102229:CLN3 protein, mouse; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; C064972:TFEB protein, human; D014199:Trehalose; C494918:AKT1 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt