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.
Authors
- Max Koppers (ORCID: https://orcid.org/0000-0002-7751-1082)
- Rianne de Jongh (ORCID: https://orcid.org/0009-0004-5530-3954)
- Alessandro Iuliano (ORCID: https://orcid.org/0009-0000-4183-1386)
- R. Jeroen Pasterkamp (ORCID: https://orcid.org/0000-0003-1631-6440)
- W.W.M. Pim Pijnappel (ORCID: https://orcid.org/0000-0002-7042-2482)
- Lauri M. Bloemenkamp
- Onur Başak (ORCID: https://orcid.org/0000-0002-6864-3403)
- Charlotte H. van Dijk (ORCID: https://orcid.org/0009-0003-2503-0038)
- Keith M. Garner
- Kevin Patrick Kenna (ORCID: https://orcid.org/0009-0001-2712-7218)
- Sofie Peeters
- Anna F. Wiersema (ORCID: https://orcid.org/0009-0000-1628-9513)
- Roos C. Verdegaal (ORCID: https://orcid.org/0009-0007-0053-2604)
- Jelle van Os (ORCID: https://orcid.org/0009-0009-0108-5564)
- Mareine M. J. Smulders
- Laura Olmedo-Martínez (ORCID: https://orcid.org/0009-0001-9828-9038)
- Sandrine Da Cruz
Institutions
- Allen Institute for Brain Science (US)
- Utrecht University (NL)
- Erasmus MC (NL)
- University Medical Center Utrecht (NL)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-15
- DOI
- https://doi.org/10.1038/s41467-026-78419-7
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Muscular Dystrophy Association
- EU Joint Programme – Neurodegenerative Disease Research
- Health~Holland
- E-Rare
- Fonds Wetenschappelijk Onderzoek
- Prinses Beatrix Spierfonds
- Alzheimer Nederland
- Vlaamse regering