GDF5 as a Multimodal Protector of the Motor Unit in Amyotrophic Lateral Sclerosis
Abstract
Amyotrophic lateral sclerosis is characterized by the progressive dismantling of the motor unit. While "dying back" hypothesis suggests that peripheral neuromuscular dysfunction precedes motor neuron loss, the molecular mechanisms limiting endogenous compensatory responses remain poorly understood. We longitudinally examined neuromuscular decline and GDF5-SMAD1/5/8 signaling in SOD1 G93A mice. Our findings revealed a translational checkpoint linked to the lncRNA Myoparr that suppresses GDF5 production at symptom onset. To overcome this deficit, we delivered AAV9-GDF5 at the symptomatic stage. GDF5 supplementation restored SMAD signaling balance, shifting the motor unit from a pro-atrophic TGF-β-SMAD2/3 toward a promyogenic SMAD1/5 profile. Treatment preserved muscle mass, reduced mitochondrial reactive oxygen species, and maintained neuromuscular junction integrity, including peri-synaptic glial support. GDF5 also promoted molecular recovery of spinal MNs by enhancing homeostatic marker expression. Together, these findings identify GDF5 as a multimodal stabilizer of the motor unit and highlight its potential as therapeutic target in combinatorial strategies aimed at coupling motor unit stabilization with central neuroprotective interventions.
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BibTeX
@misc{bourguiba2026gdf5,
title = {{GDF5 as a Multimodal Protector of the Motor Unit in Amyotrophic Lateral Sclerosis}},
author = {Aly Bourguiba and Sonia Pezet and Massiré Traoré and Christel Gentil and Thibaut Marais and Aurélie Fail and Maxime Gelin and Julien Mésseant and Pierre Meunier and Sofia Benkhelifa-Ziyyat and Zoheir Guesmia and Bruno Cadot and Antonio Musaro and Gabriella Dobrowolny and Julianne Perronnet and Sestina Falcone and Piera Smeriglio and France Piétri‐rouxel},
howpublished = {HAL},
year = {2026},
month = jul,
doi = {10.64898/2026.06.30.735251},
url = {https://hal.science/hal-05769807v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - GDF5 as a Multimodal Protector of the Motor Unit in Amyotrophic Lateral Sclerosis
AU - Aly Bourguiba
AU - Sonia Pezet
AU - Massiré Traoré
AU - Christel Gentil
AU - Thibaut Marais
AU - Aurélie Fail
AU - Maxime Gelin
AU - Julien Mésseant
AU - Pierre Meunier
AU - Sofia Benkhelifa-Ziyyat
AU - Zoheir Guesmia
AU - Bruno Cadot
AU - Antonio Musaro
AU - Gabriella Dobrowolny
AU - Julianne Perronnet
AU - Sestina Falcone
AU - Piera Smeriglio
AU - France Piétri‐rouxel
PY - 2026
DA - 2026/07/03
PB - HAL
DO - 10.64898/2026.06.30.735251
UR - https://hal.science/hal-05769807v1
AB - Amyotrophic lateral sclerosis is characterized by the progressive dismantling of the motor unit. While "dying back" hypothesis suggests that peripheral neuromuscular dysfunction precedes motor neuron loss, the molecular mechanisms limiting endogenous compensatory responses remain poorly understood. We longitudinally examined neuromuscular decline and GDF5-SMAD1/5/8 signaling in SOD1 G93A mice. Our findings revealed a translational checkpoint linked to the lncRNA Myoparr that suppresses GDF5 production at symptom onset. To overcome this deficit, we delivered AAV9-GDF5 at the symptomatic stage. GDF5 supplementation restored SMAD signaling balance, shifting the motor unit from a pro-atrophic TGF-β-SMAD2/3 toward a promyogenic SMAD1/5 profile. Treatment preserved muscle mass, reduced mitochondrial reactive oxygen species, and maintained neuromuscular junction integrity, including peri-synaptic glial support. GDF5 also promoted molecular recovery of spinal MNs by enhancing homeostatic marker expression. Together, these findings identify GDF5 as a multimodal stabilizer of the motor unit and highlight its potential as therapeutic target in combinatorial strategies aimed at coupling motor unit stabilization with central neuroprotective interventions.
ER -