SLITRK2 knockdown rescues axonal and functional neuromuscular junction deficits in human iPSC-derived mutant FUS-ALS motor neurons
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.
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BibTeX
@article{jongh2026slitrk2,
title = {{SLITRK2 knockdown rescues axonal and functional neuromuscular junction deficits in human iPSC-derived mutant FUS-ALS motor neurons}},
author = {Rianne de Jongh and Anna F. Wiersema and Charlotte H. van Dijk and Roos C. Verdegaal and Mareine M. J. Smulders and Onur Basak and Jelle van Os and Sofie Peeters and Laura Olmedo-Martínez and Lauri M. Bloemenkamp and Keith M. Garner and Sandrine Da Cruz and Max Koppers and Alessandro Iuliano and W. W. M. Pim Pijnappel and Kevin P. Kenna and R. Jeroen Pasterkamp},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78419-7},
url = {https://www.nature.com/articles/s41467-026-78419-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SLITRK2 knockdown rescues axonal and functional neuromuscular junction deficits in human iPSC-derived mutant FUS-ALS motor neurons
AU - Rianne de Jongh
AU - Anna F. Wiersema
AU - Charlotte H. van Dijk
AU - Roos C. Verdegaal
AU - Mareine M. J. Smulders
AU - Onur Basak
AU - Jelle van Os
AU - Sofie Peeters
AU - Laura Olmedo-Martínez
AU - Lauri M. Bloemenkamp
AU - Keith M. Garner
AU - Sandrine Da Cruz
AU - Max Koppers
AU - Alessandro Iuliano
AU - W. W. M. Pim Pijnappel
AU - Kevin P. Kenna
AU - R. Jeroen Pasterkamp
PY - 2026
DA - 2026/10/15
JO - Nature Communications
DO - 10.1038/s41467-026-78419-7
UR - https://www.nature.com/articles/s41467-026-78419-7
AB - 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.
SN - 2041-1723
ER -