ArticleCellular and molecular life sciences : CMLS2023
Neurofilament accumulations in amyotrophic lateral sclerosis patients' motor neurons impair axonal initial segment integrity.
Article in Cellular and molecular life sciences : CMLS, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- What can we learn on ALS pathophysiology from iPSC-derived motor neurons harbouring TARBDP mutations: a systematic review.Translational neurodegeneration · 2026Pooled it
- Appendicular Skeletal Muscle Mass and Sarcopenia as Prognostic Markers in Amyotrophic Lateral Sclerosis.Journal of cachexia, sarcopenia and muscle · 2026Article
- O-GlcNAcylation: A molecular switch linking brain health to neurodegeneration.Neural regeneration research · 2026Article
- Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics.Stem cell reports · 2026Article
- High-throughput screening of ALS patient iPSC-derived spinal motor neurons identifies novel compounds that increase neurofilament light chain expression.SLAS discovery : advancing life sciences R & D · 2026Article
- Role of Pentacyclic Triterpenes in the Management of Neurological Disorders: An Insight into Molecular Mechanisms and Therapeutic Approaches.Molecular neurobiology · 2026Review
- Investigating the Potential Roles of Environmental Exposures on the Pathology of Amyotrophic Lateral Sclerosis by Overlap Analysis.Neurotoxicity research · 2025Article
- [Advances in the Structure and Function of Neurofilament Protein and Its Application in Early Diagnosis of Amyotrophic Lateral Sclerosis].Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2025Review
- Mutations in PSEN1 predispose inflammation in an astrocyte model of familial Alzheimer's disease through disrupted regulated intramembrane proteolysis.Molecular neurodegeneration · 2025Article
- Deep learning-based segmentation in MRI-(immuno)histological examination of myelin and axonal damage in normal-appearing white matter and white matter hyperintensities.Brain pathology (Zurich, Switzerland) · 2025Article
- TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-ΔNLS model of Amyotrophic Lateral Sclerosis.Acta neuropathologica communications · 2025Article
- From Cell Architecture to Mitochondrial Signaling: Role of Intermediate Filaments in Health, Aging, and Disease.International journal of molecular sciences · 2025Review
- How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?Neurotoxicity research · 2024Review
- Article
- Metals on the Menu-Analyzing the Presence, Importance, and Consequences.Foods (Basel, Switzerland) · 2024Review
- A conserved NR5A1-responsive enhancer regulates SRY in testis-determination.Nature communications · 2024Article
- Thalamic Neuron Resilience during Osmotic Demyelination Syndrome (ODS) Is Revealed by Primary Cilium Outgrowth and ADP-ribosylation factor-like protein 13B Labeling in Axon Initial Segment.International journal of molecular sciences · 2023Article
- Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.Acta neuropathologica · 2023Article
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Authors and funding
20 authors at 4 institutions in 2 countries.
Funding
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease in adults with no curative treatment. Neurofilament (NF) level in patient' fluids have recently emerged as the prime biomarker of ALS disease progression, while NF accumulation in MNs of patients is the oldest and one of the best pathological hallmarks. However, the way NF accumulations could lead to MN degeneration remains unknown. To assess NF accumulations and study the impact on MNs, we compared MNs derived from induced pluripotent stem cells (iPSC) of patients carrying mutations in C9orf72, SOD1 and TARDBP genes, the three main ALS genetic causes. We show that in all mutant MNs, light NF (NF-L) chains rapidly accumulate in MN soma, while the phosphorylated heavy/medium NF (pNF-M/H) chains pile up in axonal proximal regions of only C9orf72 and SOD1 MNs. Excitability abnormalities were also only observed in these latter MNs. We demonstrate that the integrity of the MN axonal initial segment (AIS), the region of action potential initiation and responsible for maintaining axonal integrity, is impaired in the presence of pNF-M/H accumulations in C9orf72 and SOD1 MNs. We establish a strong correlation between these pNF-M/H accumulations, an AIS distal shift, increased axonal calibers and modified repartition of sodium channels. The results expand our understanding of how NF accumulation could dysregulate components of the axonal cytoskeleton and disrupt MN homeostasis. With recent cumulative evidence that AIS alterations are implicated in different brain diseases, preserving AIS integrity could have important therapeutic implications for ALS.
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