The study took advantage of a powerful experimental approach: generating motor neurons from induced pluripotent stem cells (iPSCs) derived from patients with FUS-ALS. These cells carry the same genetic mutation found in patients, allowing researchers to study the disease in a human cellular context rather than relying solely on animal models. Crucially, the team developed methods to separate the cell bodies from the axons of these motor neurons, enabling them to examine gene expression and RNA regulation in each compartment independently. This compartment-specific analysis revealed something unexpected: even in healthy human motor neurons, different regions of the cell use different versions of the 3′ untranslated region (3’UTR)—the portion of messenger RNA that controls protein production and localization. When the researchers compared healthy and FUS-ALS motor neurons, they found that this compartment-specific 3’UTR regulation was disrupted in the disease state, affecting genes such as SNCA, which has previously been implicated in other neurodegenerative conditions including Parkinson’s disease.

Among all the molecular changes the team detected, one stood out for its consistency and magnitude: SLITRK2, a gene encoding a protein normally involved in neuronal development and synapse formation, was strongly and repeatedly upregulated across multiple independent FUS-ALS models. This was not a chance finding in a single cell line or experimental condition; the elevation appeared reliably whenever the researchers examined motor neurons carrying FUS mutations. The consistency of this signal suggested that SLITRK2 might not simply be a bystander in the disease process but could be actively contributing to the axonal and synaptic defects that characterize early FUS-ALS pathology.

To test this hypothesis directly, the researchers used a genetic silencing technique to reduce SLITRK2 expression in the FUS-ALS motor neurons. The results were striking: lowering SLITRK2 levels normalized the axonal defects that had been observed in the diseased neurons. Axons, which in ALS patients begin to degenerate long before muscle weakness becomes apparent, showed measurable improvement when this single gene was suppressed. This finding positions SLITRK2 as a potential therapeutic target—something that could be modulated to slow or prevent the earliest stages of motor neuron decline in this form of ALS.

But axonal health is only part of the story. Motor neurons must ultimately communicate with muscle fibers through specialized connections called neuromuscular junctions, and it is the failure of these junctions that directly produces the muscle weakness and atrophy seen in ALS patients. To investigate whether SLITRK2 reduction could also rescue functional deficits at these connections, the team developed a sophisticated experimental system: a fully iPSC-derived neuromuscular junction model grown in microfluidic chips. These tiny devices compartmentalize motor neurons and muscle cells in separate chambers connected by narrow channels, allowing axons to grow toward the muscle and form functional synapses while keeping the two cell types physically separated. This setup mimics key aspects of the in vivo neuromuscular architecture and enables precise measurement of synaptic transmission.

Using this neuromuscular junction-on-a-chip system, the researchers made a nuanced discovery. When they reduced SLITRK2 in FUS-ALS motor neurons, the signaling between nerve and muscle was significantly rescued—the junctions transmitted electrical and chemical signals more effectively, approaching the levels seen in healthy connections. However, this functional improvement occurred without any change in the physical innervation of the muscle: the number and extent of nerve-muscle contacts remained the same. Additionally, the treatment did not correct the hypo-excitability of the motor neurons themselves—the reduced ability of these cells to fire electrical impulses that is another hallmark of FUS-ALS. This dissociation between functional rescue and structural or excitability correction provides important insight into the disease mechanism: SLITRK2 appears to specifically regulate the synaptic signaling machinery rather than the overall architecture of the neuromuscular junction or the intrinsic electrical properties of the motor neuron.

This selectivity is scientifically significant because it suggests that different aspects of ALS pathology—axonal degeneration, synaptic dysfunction, and altered neuronal excitability—may be driven by partially independent molecular pathways. A therapeutic strategy targeting SLITRK2 could therefore address some symptoms of the disease without necessarily correcting all of them, which has implications for how such treatments might be combined with other approaches in the future. It also underscores the value of the compartment-specific and functional assays the team developed: by measuring axonal morphology, synaptic transmission, and neuronal excitability separately, researchers can begin to disentangle the complex web of cellular defects that contribute to motor neuron loss.

Beyond the SLITRK2 finding itself, the study makes several broader contributions to ALS research. The detailed mapping of compartment-specific 3’UTR expression in human motor neurons provides a reference dataset that other researchers can use to investigate RNA regulation in both healthy and diseased states. The identification of altered 3’UTR isoforms in genes like SNCA across different cellular compartments suggests that RNA processing defects may be a common thread connecting multiple forms of neurodegeneration, not just FUS-ALS. And the fully iPSC-derived neuromuscular junction-on-a-chip model represents a robust new tool for the field—one that can be used to test potential therapeutics in a human-relevant system before moving to animal studies or clinical trials, potentially accelerating the drug development pipeline for this devastating disease.

The work was supported by funding from Stichting ALS Nederland through several collaborative projects, the European research consortia MAXOMOD and INTEGRALS, the ALS CURE project, Alzheimer Nederland, the EU Joint Programme for Neurodegenerative Diseases, Health-Holland, the Netherlands Organization for Scientific Research, the Research Foundation-Flanders, and the Muscular Dystrophy Association. The research team included contributors from the University Medical Center Utrecht Brain Center, the VIB-KU Leuven Center for Neuroscience, Utrecht University, and Erasmus MC University Medical Center in Rotterdam. The corresponding author, R. Jeroen Pasterkamp, led the study from the Department of Translational Neuroscience in Utrecht.

While the findings are promising, they represent an early step in a long translational journey. The experiments were conducted in laboratory-grown human cells, and translating these results into treatments for patients will require extensive further research, including validation in animal models and eventually clinical testing. Nevertheless, the identification of SLITRK2 as a driver of axonal and synaptic deficits in FUS-ALS provides researchers with a concrete molecular target and a clearer picture of how this form of ALS begins its destructive course. As the field continues to unravel the complex biology of motor neuron degeneration, studies like this one—combining human stem cell models, compartment-specific molecular analysis, and functional neuromuscular junction assays—are helping to build the foundation for future therapies that might one day slow, halt, or even reverse the progression of ALS.

Subject of Research: SLITRK2 regulation of axonal and neuromuscular junction deficits in FUS-ALS motor neurons

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

Article References: de Jongh, R., Wiersema, A. F., van Dijk, C. H., Verdegaal, R. C., Smulders, M. M. J., Basak, O., van Os, J., Peeters, S., Olmedo-Martínez, L., Bloemenkamp, L. M., Garner, K. M., Da Cruz, S., Koppers, M., Iuliano, A., Pijnappel, W. W. M. P., Kenna, K. P., & Pasterkamp, R. J. (2026). SLITRK2 knockdown rescues axonal and functional neuromuscular junction deficits in human iPSC-derived mutant FUS-ALS motor neurons. Nature Communications. https://doi.org/10.1038/s41467-026-78419-7

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78419-7

Keywords: ALS, FUS, SLITRK2, motor neurons, iPSC, neuromuscular junction, axons, 3'UTR, SNCA, neurodegeneration, microfluidics, synaptic signaling