Overexpression of TFEB Drives a Pleiotropic Neurotrophic Effect and Prevents Parkinson's Disease-Related Neurodegeneration

Albert Torra, Annabelle Parent, Thais Cuadros, Beatriz Rodríguez-Galván, Esther Ruiz-Bronchal, Andrea Ballabio, Analía Bortolozzi, Miquel Vila, Jordi Bové

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

© 2018 The American Society of Gene and Cell Therapy The possible implication of transcription factor EB (TFEB) as a therapeutic target in Parkinson's disease has gained momentum since it was discovered that TFEB controls lysosomal biogenesis and autophagy and that its activation might counteract lysosomal impairment and protein aggregation. However, the majority of putative direct targets of TFEB described to date is linked to a range of biological processes that are not related to the lysosomal-autophagic system. Here, we assessed the effect of overexpressing TFEB with an adeno-associated viral vector in mouse substantia nigra dopaminergic neurons. We demonstrate that TFEB overexpression drives a previously unknown bona fide neurotrophic effect, giving rise to cell growth, higher tyrosine hydroxylase levels, and increased dopamine release in the striatum. TFEB overexpression induces the activation of the mitogen-activated protein kinase 1/3 (MAPK1/3) and AKT pro-survival pathways, phosphorylation of mTORC1 effectors 4E-binding protein 1 (4E-BP1) and S6 kinase B1 (S6K1), and increased protein synthesis. We show that TFEB overexpression prevents dopaminergic cell loss and counteracts atrophy and the associated protein synthesis decline in the MPTP mouse model of Parkinson's disease. Our results suggest that increasing TFEB activity might prevent neuronal death and restore neuronal function in Parkinson's disease and other neurodegenerative diseases through different mechanisms. Torra et al. demonstrate that transcription factor EB (TFEB) overexpression drives a bona fide neurotrophic effect in mice dopaminergic neurons that counteracts neuronal death, atrophy, and dysfunction in a Parkinson's disease model. They show that TFEB overexpression effect goes beyond autophagy and involves the activation of different pro-survival pathways.
Original languageEnglish
Pages (from-to)1552-1567
JournalMolecular Therapy
Volume26
Issue number6
DOIs
Publication statusPublished - 6 Jun 2018

Keywords

  • MPTP
  • Parkinson's disease
  • TFEB
  • dopamine
  • neuronal atrophy
  • neuroprotection
  • neurorescue
  • neurotrophic
  • prosurvival pathways

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