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.

HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models / Silvestri, Beatrice; Mochi, Michela; Mawrie, Darilang; DE TURRIS, Valeria; Colantoni, Alessio; Borhy, Beatrice; Medici, Margherita; Nathaniel Anderson, Eric; Giovanna Garone, Maria; Patrick Zammerilla, Christopher; Simula, Marco; Ballarino, Monica; Bhan Pandey &, Udai; Rosa, Alessandro. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 15(2024). [10.1038/s41467-024-54004-8]

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

Michela Mochi
Secondo
Formal Analysis
;
Valeria de Turris
Methodology
;
Alessio Colantoni
Formal Analysis
;
Beatrice Borhy
Methodology
;
Margherita Medici
Methodology
;
Marco Simula
Methodology
;
Monica Ballarino
Supervision
;
Alessandro Rosa
Ultimo
Writing – Original Draft Preparation
2024

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.
2024
Amyotrophic lateral sclerosis; Animal disease models; Induced pluripotent stem cells; RNA metabolism
01 Pubblicazione su rivista::01a Articolo in rivista
HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models / Silvestri, Beatrice; Mochi, Michela; Mawrie, Darilang; DE TURRIS, Valeria; Colantoni, Alessio; Borhy, Beatrice; Medici, Margherita; Nathaniel Anderson, Eric; Giovanna Garone, Maria; Patrick Zammerilla, Christopher; Simula, Marco; Ballarino, Monica; Bhan Pandey &, Udai; Rosa, Alessandro. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 15(2024). [10.1038/s41467-024-54004-8]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1726546
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