Work

SLITRK2 knockdown rescues axonal and functional neuromuscular junction deficits in human iPSC-derived mutant FUS-ALS motor neurons

Year: 2026

Type: article

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) loss caused by early axonal and synaptic changes. However, the mechanisms underlying these changes remain incompletely understood. Here, we exploit FUS-ALS to interrogate cell compartment-specific changes in RNA expression and regulation in human induced pluripotent stem cell (iPSC)-derived MN. This approach identifies compartment-specific 3’ untranslated region (3’UTR) isoform expression in human healthy control MN axons. Further, it unveils altered 3’ UTR isoforms in ALS in different cellular compartments in genes such as SNCA , previously linked to neurodegeneration. Expression of SLITRK2 is most strongly and consistently upregulated across multiple FUS-ALS models, and its knockdown normalizes axonal defects linked to FUS-ALS. Using a fully iPSC-derived neuromuscular microfluidics protocol, we show that SLITRK2 knockdown in FUS-ALS MN rescues neuromuscular junction (NMJ) signaling without affecting NMJ innervation or MN hypo-excitability. Our study provides insight into compartment-specific 3’UTR expression in ALS, presents a robust iNMJ-on-a-chip model, and links elevated SLITRK2 to axonal and synaptic defects in FUS-ALS.

Source: Nature Communications

DOI: 10.1038/s41467-026-78419-7