Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies.

Marie-Laure Arotcarena,Benjamin Dehay,Wassilios G Meissner,Evelyne Doudnikoff,Nathalie Dutheil,Erwan Bezard,Andrea Ballabio,Sandra Dovero,Pierre-Olivier Fernagut,Mathieu Bourdenx,Marie-Laure Thiolat

doi:10.1172/jci.insight.129719

Marie-Laure Arotcarena, Benjamin Dehay + Show 9 more

Open Access

https://doi.org/10.1172/jci.insight.129719

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Journal: JCI insight	Publication Date: Aug 22, 2019
Citations: 58	License type: CC BY 4.0

Affiliation: University of Bordeaux, University of Poitiers

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.

Highlights

Synucleinopathies are a heterogenous group of neurodegenerative diseases characterized by the formation of α-synuclein (α-syn) aggregates
Since transcription factor EB (TFEB) overexpression has been shown to be neuroprotective against AAV-mediated WT α-syn overexpression in rats [23], we first aimed at extending this observation through the assessment of the effects of increasing the autophagy-lysosomal pathways (ALP) through TFEB overexpression in a rat model of Parkinson’s disease (PD) based, this time, on the overexpression of human mutated A53T–α-syn
Four months after stereotactic surgery, we observed that coinjection of AAV-TFEB and AAV–A53T–αsyn was able to prevent behavioral impairments induced in this model of PD

Summary

Introduction

Synucleinopathies are a heterogenous group of neurodegenerative diseases characterized by the formation of α-synuclein (α-syn) aggregates. Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and is characterized by motor and nonmotor symptoms. The main neuropathological hallmark of PD is the presence of neuronal α-syn–positive intracytoplasmic inclusions named Lewy bodies (LB) in cell bodies and Lewy neurites in cell processes [1]. Multiple system atrophy (MSA) is a rare, fast-progressing disease divided in 2 clinical phenotypes: (a) the MSA parkinsonian showing L-3,4-dihydroxyphenylalanine nonresponsive parkinsonian syndrome with bradykinesia, rigidity, and rest tremor due to a dopaminergic loss in the nigrostriatal pathway; and (b) the MSA cerebellar exhibiting cerebellar syndrome with gait, speech, and limb ataxia, and cerebellar oculomotor dysfunction caused by a neuronal loss in the olivopontocerebellar pathway. The neuropathological hallmark of MSA is the presence of α-syn–positive cytoplasmic inclusions, in oligodendrocytes, named glial cytoplasmic inclusions [2]

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