Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies
Marie-Laure Arotcarena, Mathieu Bourdenx, Nathalie Dutheil, Marie-Laure Thiolat, Evelyne Doudnikoff, Sandra Dovero, Andrea Ballabio, Pierre-Olivier Fernagut, Wassilios G. Meissner, Erwan Bezard, Benjamin Dehay
Marie-Laure Arotcarena, Mathieu Bourdenx, Nathalie Dutheil, Marie-Laure Thiolat, Evelyne Doudnikoff, Sandra Dovero, Andrea Ballabio, Pierre-Olivier Fernagut, Wassilios G. Meissner, Erwan Bezard, Benjamin Dehay
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Research Article Neuroscience Therapeutics

Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies

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.

Authors

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

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Figure 7

Both oligodendroglial– and neuronal TFEB–targeted overexpression induce neurotrophic effects in the brains of PLP mice.

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Both oligodendroglial– and neuronal TFEB–targeted overexpression induce ...
(A and B) Representative images (A) and quantification (B) of TH-positive immunostaining in the ipsilateral SN of control, CMVie/hSyn-mTFEB–injected, and MBP-mTFEB–injected WT and PLP mice. Scale bar: 50 μm. (C) Linear regression between TH-positive immunostaining and TH- and Nissl-positive cells in the SN of control WT (empty dark dots) and PLP mice (full dark dots). (D) Ratio of TH-positive immunostaining in the ipsilateral SN divided by the number of TH- and Nissl-positive neurons into the ipsilateral SN of control, CMVie/hSyn-mTFEB–injected, and MBP-mTFEB- injected WT and PLP mice. n = 5 per group. White bars, control; blue bars, CMVie/hSyn-mTFEB-HA; green bars, MBP-mTFEB-3×Flag. (E) Scatter plot of the value of TH surface immunostaining and the number of TH- and Nissl-positive neurons into the ipsilateral SN of control, CMVie/hSyn-mTFEB–injected, and MBP-mTFEB–injected WT and PLP mice. Each dot represents 1 animal. Red dot corresponds to the center of mass of each experimental group, and the ellipses represent the 95% CI around the center of mass: PLP control (black); CMVie/hSyn-mTFEB PLP (blue); MBP-mTFEB-PLP (green). Dashed lines are arbitrarily centered on the center of mass of PLP control group to distinguish between neurotrophic effect (toward upper left quadrant), neuroprotection (lower right quadrant), and a combination of both (upper right quadrant) in AAV-injected PLP groups; black arrows represent the direction of the change. Data represent mean ± SEM. Comparisons were made using 2-way ANOVA and Tukey’s correction for multiple comparisons. *P < 0.05 compared with control PLP animals. $P < 0.05 compared with control WT animals.