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HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models

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  • Beatrice Silvestri

    (Sapienza University of Rome
    Fondazione Istituto Italiano di Tecnologia (IIT)
    Sanford Burnham Prebys Medical Discovery Institute)

  • Michela Mochi

    (Sapienza University of Rome)

  • Darilang Mawrie

    (University of Pittsburgh Medical Center)

  • Valeria de Turris

    (Fondazione Istituto Italiano di Tecnologia (IIT))

  • Alessio Colantoni

    (Sapienza University of Rome
    Fondazione Istituto Italiano di Tecnologia (IIT))

  • Beatrice Borhy

    (Sapienza University of Rome)

  • Margherita Medici

    (Sapienza University of Rome)

  • Eric Nathaniel Anderson

    (University of Pittsburgh Medical Center)

  • Maria Giovanna Garone

    (Murdoch Children’s Research Institute
    reNEW Melbourne, Murdoch Children’s Research Institute)

  • Christopher Patrick Zammerilla

    (University of Pittsburgh Medical Center)

  • Marco Simula

    (Sapienza University of Rome)

  • Monica Ballarino

    (Sapienza University of Rome)

  • Udai Bhan Pandey

    (University of Pittsburgh Medical Center
    University of Pittsburgh Medical Center)

  • Alessandro Rosa

    (Sapienza University of Rome
    Fondazione Istituto Italiano di Tecnologia (IIT))

Abstract

Defects at the neuromuscular junction (NMJ) are among the earliest hallmarks of amyotrophic lateral sclerosis (ALS). According to the “dying-back” hypothesis, NMJ disruption not only precedes but also triggers the subsequent degeneration of motoneurons in both sporadic (sALS) and familial (fALS) ALS. Using human induced pluripotent stem cells (iPSCs), we show that the RNA-binding protein HuD (ELAVL4) contributes to NMJ defects and apoptosis in FUS-ALS. HuD overexpression mimics the severe FUSP525L mutation, while its knockdown rescues the FUSP525L phenotypes. In Drosophila, neuronal overexpression of the HuD ortholog, elav, induces motor dysfunction, and its knockdown improves motor function in a FUS-ALS model. Finally, we report increased HuD levels upon oxidative stress in human motoneurons and in sALS patients with an oxidative stress signature. Based on these findings, we propose that HuD plays a role downstream of FUS mutations in fALS and in sALS related to oxidative stress.

Suggested Citation

  • Beatrice Silvestri & Michela Mochi & Darilang Mawrie & Valeria de Turris & Alessio Colantoni & Beatrice Borhy & Margherita Medici & Eric Nathaniel Anderson & Maria Giovanna Garone & Christopher Patric, 2024. "HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54004-8
    DOI: 10.1038/s41467-024-54004-8
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