Researchers uncover a new communication pathway that may help protect neuromuscular junctions in ALS

ALS is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Research by Prof. Perlson and colleagues reveals that muscle-derived extracellular vesicles (EVs), containing a small regulatory molecule called miR-126-5p, deliver this molecule directly to motor neuron terminals, where it suppresses the local production of TDP-43, a protein closely linked to ALS pathology.

Using mouse models, human patient samples, and stem cell-derived human neuromuscular systems, the team demonstrated that reduced miR-126-5p levels are associated with ALS. Importantly, restoring miR-126-5p delayed the accumulation of toxic TDP-43, preserved neuromuscular connections, and improved motor performance in ALS mice. The protective effects were also observed in human cell models carrying ALS-associated mutations.

The findings highlight the importance of local protein regulation at individual NMJs. According to the researchers, targeting miR-126-5p or related signaling pathways could open new avenues for developing treatments aimed at slowing disease progression and preserving motor function in patients with ALS.

Read the full paper:

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

Published in: Nature Neuroscience

Authors: 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

https://www.nature.com/articles/s41593-025-02062-6