ArticleNature communications2025
Sporadic ALS induced pluripotent stem cell derived neurons reveal hallmarks of TDP-43 loss of function.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Intron retention in health and amyotrophic lateral sclerosis.Brain : a journal of neurology · 2026Review
- Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.Journal of neurology · 2026Review
- TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.Biochemical Society transactions · 2026Review
- TDP-43 dysfunction facilitates the pathological conversion of tau.Molecular neurodegeneration · 2026Article
- Article
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.bioRxiv : the preprint server for biology · 2026Article
- Review of the Pathology of Muscle in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2026Review
- Review
- Experimental Models and Translational Strategies in Neuroprotective Drug Development with Emphasis on Alzheimer's Disease.Molecules (Basel, Switzerland) · 2026Review
- Identification of molecular and clinical ALS subgroups based on TDP-43 loss of function molecular markers from population-based patient-derived iPS motor neurons.bioRxiv : the preprint server for biology · 2026Article
- Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction.bioRxiv : the preprint server for biology · 2025Article
- Molecular Visualization of Neuronal TDP43 PathologybioRxiv : the preprint server for biology · 2025Article
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Authors and funding
7 authors.
Funding
Abstract
Nuclear loss and cytoplasmic buildup of the RNA-binding protein TDP-43 is a hallmark of ALS and related disorders. While studies using artificial TDP-43 depletion in neurons have revealed changes in gene expression and splicing, their relevance to actual patients remained unclear. Induced pluripotent stem cell (iPSC)-derived neurons (iPSNs) from 180 individuals, including controls, C9orf72 ALS/FTD, and sporadic ALS (sALS) patients were used to generate and analyze ~32,500 qRT-PCR data points across 20 genes which identified variable, time-dependent signatures of TDP-43 loss of function in individual lines. Notably, the same changes were also seen in postmortem brain tissue from the same patients, confirming that iPSNs accurately model disease. Inducing damage to the nuclear pore complex, specifically by reducing the nucleoporin POM121 in healthy iPSNs, was enough to replicate the molecular changes associated with ALS/FTD TDP-43 dysfunction. This directly links nuclear pore integrity to TDP-43-related pathology. Encouragingly, repairing nuclear pore injury in sALS iPSNs restored normal gene processing disrupted by TDP-43 loss. This study (1) provides a valuable population-scale resource for studying TDP-43 dysfunction in ALS, (2) confirms that patient-derived iPSNs closely reflect disease processes seen in the brain, and (3) demonstrates that targeting nuclear pore injury may offer a promising therapeutic strategy in ALS.
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