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Mol Ther. 2018 Jun 6;26(6):1552-1567. doi: 10.1016/j.ymthe.2018.02.022. Epub 2018 Feb 27.

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

Author information

1
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain.
2
Department of Neurochemistry and Neuropharmacology, IIBB-CSIC, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Center for Networked Biomedical Research on Mental Health (CIBERSAM), Barcelona, Catalonia, Spain.
3
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
4
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain; Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Catalonia, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain. Electronic address: miquel.vila@vhir.org.
5
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain. Electronic address: jordi.bove@vhir.org.

Abstract

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.

KEYWORDS:

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

PMID:
29628303
PMCID:
PMC5986717
DOI:
10.1016/j.ymthe.2018.02.022

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