ArticleMolecular neurodegeneration2023
FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms.
Article in Molecular neurodegeneration, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 60 citations in OpenAlex.
- A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.NPJ systems biology and applications · 2025Pooled it
- Rapid generation of human sensory neurons from iPSC for modeling of peripheral neuropathies.Journal of neuroscience methods · 2026Article
- TDP-43-immunity-microbiota axis in amyotrophic lateral sclerosis: A potential pathogenic mechanism.Neural regeneration research · 2026Article
- Review
- Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.Cell communication and signaling : CCS · 2026Article
- ALS-FTD-linked CCNFJournal of neuroinflammation · 2026Article
- Large-scale mapping of the MCH network in ALS mice reveals the vulnerability of dopaminergic and GABAergic neurons in zona incerta.Acta neuropathologica communications · 2026Article
- Hypoxic stress is an early pathogenic event in human VCP-mutant ALS astrocytes.Stem cell reports · 2026Article
- Retrospective Study of the Physiological and Molecular Features of the S-FUS (1-359) Mouse Transgenic Model with an ALS-like Phenotype: Lifespan, Body Weight Dynamics, Movement Disorders, and Dysregulation of the Dopaminergic System.Journal of molecular neuroscience : MN · 2026Article
- Disrupted astrocyte-neuron metabolic coupling in amyotrophic lateral sclerosis.Frontiers in cell and developmental biology · 2026Review
- Syntaphilin loss enhances mitochondrial axonal transport and neuromuscular junction formation in a human stem cell derived neuromuscular assembloid model.Molecular medicine (Cambridge, Mass.) · 2025Article
- Novel Dual Mechanism GRT-X Agonist Acting on Kv7 Potassium Channel/Translocator Protein Receptor Prevents Motoneuron Degeneration Following Exposure to Mouse and Human Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Astrocyte-Conditioned Media.ACS chemical neuroscience · 2025Article
- Glycerophospholipids in ALS: insights into disease mechanisms and clinical implication.Molecular neurodegeneration · 2025Review
- The Collapse of Brain Clearance: Glymphatic-Venous Failure, Aquaporin-4 Breakdown, and AI-Empowered Precision Neurotherapeutics in Intracranial Hypertension.International journal of molecular sciences · 2025Review
- Inorganic Polyphosphate: An Emerging Regulator of Neuronal Bioenergetics and Its Implications in Neuroprotection.Biomolecules · 2025Review
- Analysis of astrocyte progenitors derived from human induced pluripotent stem cellsbioRxiv : the preprint server for biology · 2025Article
- C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis.Brain : a journal of neurology · 2025Article
- Integrated transcriptomic profiling reveals a STING-mediated Type II Interferon signature in SOD1-mutant amyotrophic lateral sclerosis models.Communications biology · 2025Article
- Review
- Modeling ALS with Patient-Derived iPSCs: Recent Advances and Future Potentials.Brain sciences · 2025Review
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAstrocytes play a crucial, yet not fully elucidated role in the selective motor neuron pathology in amyotrophic lateral sclerosis (ALS). Among other responsibilities, astrocytes provide important neuronal homeostatic support, however this function is highly compromised in ALS. The establishment of fully human coculture systems can be used to further study the underlying mechanisms of the dysfunctional intercellular interplay, and has the potential to provide a platform for revealing novel therapeutic entry points.
methodsIn this study, we characterised human induced pluripotent stem cell (hiPSC)-derived astrocytes from FUS-ALS patients, and incorporated these cells into a human motor unit microfluidics model to investigate the astrocytic effect on hiPSC-derived motor neuron network and functional neuromuscular junctions (NMJs) using immunocytochemistry and live-cell recordings. FUS-ALS cocultures were systematically compared to their CRISPR-Cas9 gene-edited isogenic control systems.
resultsWe observed a dysregulation of astrocyte homeostasis, which resulted in a FUS-ALS-mediated increase in reactivity and secretion of inflammatory cytokines. Upon coculture with motor neurons and myotubes, we detected a cytotoxic effect on motor neuron-neurite outgrowth, NMJ formation and functionality, which was improved or fully rescued by isogenic control astrocytes. We demonstrate that ALS astrocytes have both a gain-of-toxicity and loss-of-support function involving the WNT/β-catenin pathway, ultimately contributing to the disruption of motor neuron homeostasis, intercellular networks and NMJs.
conclusionsOur findings shine light on a complex, yet highly important role of astrocytes in ALS, and provides further insight in to their pathological mechanisms.
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