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<p>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<sup>G93A</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • 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

摘要

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 SOD1G93A 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.