Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models

Ariel Ionescu; Lior Ankol; Anand Ganapathy Subramaniam; Topaz Altman; Iddo Magen; Yahel Cohen; Yehuda Danino; Tal Gradus-Pery; Yoav Niv; Ori Bar Avi; Danielle Geller; Amjd Ibraheem; Ruilei Cheng; Noam Steinberg; Leenor Alfahel; Pauline Duc; Zeynep Ergul-Ulger; Doruk Arslan; Ersin Tan; Florence Rage; Nilo Riva; Angello Quattrini; Can Ebru Bekircan-Kurt; Adrian Israelson; Amir Dori; Eran Hornstein; Eran Perlson

doi:10.1038/s41593-025-02062-6

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Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models

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Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models

Ariel Ionescu, Lior Ankol, Anand Ganapathy Subramaniam, Topaz Altman, Iddo Magen, Yahel Cohen, Yehuda Danino, Tal Gradus-Pery, Yoav Niv, Ori Bar Avi, …

Nature neuroscience, Vol.28(11), pp.2201-2216

11/2025

DOI: https://doi.org/10.1038/s41593-025-02062-6

PMID: 41044342

Résumé

Amyotrophic Lateral Sclerosis - genetics

Amyotrophic Lateral Sclerosis - metabolism

Amyotrophic Lateral Sclerosis - pathology

Animals

Axons - metabolism

Axons - pathology

Disease Models, Animal

DNA-Binding Proteins - biosynthesis

DNA-Binding Proteins - genetics

DNA-Binding Proteins - metabolism

Extracellular Vesicles - metabolism

Humans

Induced Pluripotent Stem Cells - metabolism

Male

Mice

Mice, Transgenic

MicroRNAs - genetics

MicroRNAs - metabolism

Motor Neurons - metabolism

Muscle, Skeletal - metabolism

Neuromuscular Junction - metabolism

Neuromuscular Junction - pathology

Superoxide Dismutase-1 - genetics

Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TAR DNA-binding protein 43 (TDP-43) in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms that drive local TDP-43 accumulation remain unknown. Here we identify that the TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stems from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p extracellular vesicles (EVs). Inhibiting muscle secretion of miR-126a-5p prompts presynaptic TDP-43 synthesis and accumulation, which disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1 mice, primary co-cultures and human induced pluripotent stem cell (iPSC)-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance, offering insights into ALS onset and progression.

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Titre: Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models
Créateurs - sans rôle: Ariel Ionescu - Tel Aviv University
Lior Ankol - Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
Anand Ganapathy Subramaniam - Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
Topaz Altman - Tel Aviv University
Iddo Magen - Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
Yahel Cohen - Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
Yehuda Danino - Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
Tal Gradus-Pery - Tel Aviv University
Yoav Niv - Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
Ori Bar Avi - Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
Danielle Geller - Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
Amjd Ibraheem - Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
Ruilei Cheng - Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
Noam Steinberg - Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
Leenor Alfahel - The School of Brain Sciences and Cognition, Ben-Gurion University of the Negev, Beersheba, Israel
Pauline Duc - Institut de Génétique Moléculaire de Montpellier
Zeynep Ergul-Ulger - Department of Neurology, Neuromuscular Diseases Research Laboratory, Hacettepe University, Altındağ, Turkey
Doruk Arslan - Department of Neurology, Neuromuscular Diseases Research Laboratory, Hacettepe University, Altındağ, Turkey
Ersin Tan - Department of Neurology, Neuromuscular Diseases Research Laboratory, Hacettepe University, Altındağ, Turkey
Florence Rage - Institut de Génétique Moléculaire de Montpellier
Nilo Riva - 3rd Neurology Unit and Motor Neuron Disease Centre, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Angello Quattrini - Institute of Experimental Neurology (INSPE), IRCCS San Raffaele Scientific Institute, Milan, Italy
Can Ebru Bekircan-Kurt - Department of Neurology, Neuromuscular Diseases Research Laboratory, Hacettepe University, Altındağ, Turkey
Adrian Israelson - The School of Brain Sciences and Cognition, Ben-Gurion University of the Negev, Beersheba, Israel
Amir Dori - Department of Neurology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
Eran Hornstein - Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
Eran Perlson - Tel Aviv University
Détails de publication: Nature neuroscience, Vol.28(11), pp.2201-2216
Identifiants: 99139809809311
Unité académique: Institut de Génétique Moléculaire de Montpellier - IGMM
Langue: English
Type de ressource: Journal article