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Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies

Arotcarena, Marie-Laure, Bourdenx, Mathieu, Dutheil, Nathalie, Thiolat, Marie-Laure, Doudnikoff, Evelyne, Dovero, Sandra, Ballabio, Andrea, Fernagut, Pierre-Olivier, Meissner, Wassilios G., Bezard, Erwan, Dehay, Benjamin·2019·JCI Insight
DOI 10.1172/jci.insight.129719PMC PMC6777809
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Abstract

The synucleinopathies Parkinson’s disease (PD) and Multiple system atrophy (MSA) — characterized by α-synuclein intracytoplasmic inclusions into, respectively, neurons and oligodendrocytes — are associated with impairment of the autophagy-lysosomal pathways (ALP). Increased expression of the master regulator of ALP, transcription factor EB (TFEB), is hypothesized to promote the clearance of WT α-synuclein and survival of dopaminergic neurons. Here, we explore the efficacy of targeted TFEB overexpression either in neurons or oligodendrocytes to reduce the pathological burden of α-synuclein in a PD rat model and a MSA mouse model. While TFEB neuronal expression was sufficient to prevent neurodegeneration in the PD model, we show that only TFEB oligodendroglial overexpression leads to neuroprotective effects in the MSA model. These beneficial effects were associated with a decreased accumulation of α-synuclein into oligodendrocytes through recovery of the ALP machinery. Our study demonstrates that the cell type where α-synuclein aggregates dictates the target of TFEB overexpression in order to be protective, paving the way for adapted therapies.

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Metadata

Authors
Arotcarena, M.-L., Bourdenx, M., Dutheil, N., Thiolat, M.-L., Doudnikoff, E., Dovero, S., Ballabio, A., Fernagut, P.-O., Meissner, W. G., Bezard, E., & Dehay, B.
Affiliations
  • Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (Naples), Italy.
  • Laboratoire de Neurosciences Expérimentales et Cliniques, INSERM U-1084, Université de Poitiers, Poitiers, France.
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2019-08-22
Volume
4
Issue
16
ISSN
2379-3708
DOI
10.1172/jci.insight.129719
PMC
PMC6777809
Cited by
84
References
9
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
The LABEX Brain, the University of Bordeaux and the Centre National de la Recherche Scientifique (None)

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