Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies.
Aged
Animals
Autophagy
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
/ metabolism
Brain
/ metabolism
Cell Line, Tumor
Disease Models, Animal
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Multiple System Atrophy
/ metabolism
Oligodendroglia
/ metabolism
Parkinson Disease
/ metabolism
Rats
Rats, Sprague-Dawley
alpha-Synuclein
/ metabolism
Autophagy
Gene therapy
Neuroscience
Parkinson’s disease
Therapeutics
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
22 08 2019
22 08 2019
Historique:
received:
22
04
2019
accepted:
11
07
2019
entrez:
23
8
2019
pubmed:
23
8
2019
medline:
18
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31434803
pii: 129719
doi: 10.1172/jci.insight.129719
pmc: PMC6777809
doi:
pii:
Substances chimiques
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
0
TFEB protein, human
0
TFEB protein, rat
0
Tcfeb protein, mouse
0
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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