mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases.
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.
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Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Trealose
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Fármacos Neuroprotetores
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Doenças Neurodegenerativas
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Proteínas Proto-Oncogênicas c-akt
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article