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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.
Afiliação
  • Arotcarena ML; Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Bourdenx M; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Dutheil N; Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Thiolat ML; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Doudnikoff E; Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Dovero S; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Ballabio A; Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Fernagut PO; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Meissner WG; Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Bezard E; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
  • Dehay B; Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
JCI Insight ; 4(16)2019 08 22.
Article em En | MEDLINE | ID: mdl-31434803
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Atrofia de Múltiplos Sistemas / Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos Tipo de estudo: Prognostic_studies Limite: Aged / Animals / Humans / Male Idioma: En Revista: JCI Insight Ano de publicação: 2019 Tipo de documento: Article País de afiliação: França

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Atrofia de Múltiplos Sistemas / Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos Tipo de estudo: Prognostic_studies Limite: Aged / Animals / Humans / Male Idioma: En Revista: JCI Insight Ano de publicação: 2019 Tipo de documento: Article País de afiliação: França