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

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 FUS^P525L mutation, while its knockdown rescues the FUS^P525L 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 st

SUBMITTER: Silvestri B 

PROVIDER: S-EPMC11544248 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature