HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models
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 FUS<sup>P525L</sup> mutation, while its knockdown rescues the FUS<sup>P525L</sup> 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.
Authors
- Alessio Colantoni (ORCID: https://orcid.org/0000-0001-7402-0176)
- Alessandro Rosa (ORCID: https://orcid.org/0000-0001-9999-7223)
- Beatrice Silvestri
- Darilang Mawrie
- Maria Giovanna Garone (ORCID: https://orcid.org/0000-0002-2101-4474)
- Margherita Medici
- Eric N. Anderson (ORCID: https://orcid.org/0000-0003-2533-8764)
- Michela Mochi
- Udai Bhan Pandey (ORCID: https://orcid.org/0000-0002-6267-0179)
- Monica Ballarino (ORCID: https://orcid.org/0000-0002-8595-7105)
- Valeria de Turris (ORCID: https://orcid.org/0000-0003-0872-185X)
- Beatrice Borhy
- Christopher Patrick Zammerilla
- Maria E. Simula
Institutions
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Discovery Institute (US)
- Italian Institute of Technology (IT)
- Children's Hospital of Pittsburgh (US)
- University of Pittsburgh Medical Center (US)
- Murdoch Children's Research Institute (AU)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1038/s41467-024-54004-8
- Citations
- 4
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 1.48
Funders
- Wellcome Trust
- European Federation of Pharmaceutical Industries and Associations
- European Commission
- Istituto Italiano di Tecnologia
- National Institutes of Health