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mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases.
Palmieri, Michela; Pal, Rituraj; Nelvagal, Hemanth R; Lotfi, Parisa; Stinnett, Gary R; Seymour, Michelle L; Chaudhury, Arindam; Bajaj, Lakshya; Bondar, Vitaliy V; Bremner, Laura; Saleem, Usama; Tse, Dennis Y; Sanagasetti, Deepthi; Wu, Samuel M; Neilson, Joel R; Pereira, Fred A; Pautler, Robia G; Rodney, George G; Cooper, Jonathan D; Sardiello, Marco.
Afiliação
  • Palmieri M; 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.
  • Pal R; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Nelvagal HR; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London SE5 9RT, UK.
  • Lotfi P; 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.
  • Stinnett GR; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Seymour ML; Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Chaudhury A; Department of Molecular Physiology and Biophysics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Bajaj L; 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.
  • Bondar VV; 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.
  • Bremner L; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London SE5 9RT, UK.
  • Saleem U; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology &Neuroscience, King's College London, London SE5 9RT, UK.
  • Tse DY; Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Sanagasetti D; School of Optometry, The Hong Kong Polytechnic University, Kowloon, Hong Kong.
  • Wu SM; 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.
  • Neilson JR; Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Pereira FA; Department of Molecular Physiology and Biophysics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Pautler RG; Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Rodney GG; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Cooper JD; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
  • Sardiello M; Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
Nat Commun ; 8: 14338, 2017 02 06.
Article em En | MEDLINE | ID: mdl-28165011
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Trealose / Fármacos Neuroprotetores / Doenças Neurodegenerativas / Proteínas Proto-Oncogênicas c-akt / Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Trealose / Fármacos Neuroprotetores / Doenças Neurodegenerativas / Proteínas Proto-Oncogênicas c-akt / Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos Idioma: En Ano de publicação: 2017 Tipo de documento: Article