Nature communicationsAug 2, 2025

Neurons made from stem cells of sporadic ALS patients show signs of TDP-43 protein loss

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Updated Mar 25, 2026

Abstract

Analysis of ~32,500 qRT-PCR data points across 20 genes from -derived neurons identified variable, time-dependent signatures of loss of function in 180 individuals.

Nuclear loss and cytoplasmic buildup of TDP-43 is a characteristic feature of ALS and related disorders.
Changes in gene expression and splicing observed in artificially depleted TDP-43 neurons were confirmed in patient-derived cells.
Molecular changes associated with TDP-43 dysfunction were also present in postmortem brain tissue from the same patients.
Reducing the nucleoporin POM121 in healthy neurons replicated the molecular changes seen in ALS/FTD.
Repairing nuclear pore damage in sporadic ALS neurons restored normal gene processing affected by TDP-43 loss.

Simplified

Nuclear loss and cytoplasmic buildup of the RNA-binding protein 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 ()-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 , 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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Competing interests

Competing interests: A.N.C. (50%) and J.D.R. (50%) are inventors on US patent application number 63/111,882 filed by Johns Hopkins University on methods to modulate CHMP7 expression as a therapy for neurodegeneration. A.N.C. (75%) and J.D.R. (25%) are inventors on US patent application number 63/605,054 filed by Johns Hopkins University on methods to increase/restore expression of POM121 for mitigation of NPC injury and TDP-43 dysfunction in neurodegeneration. The remaining authors declare no competing interests.

PubMed

Neurons made from stem cells of sporadic ALS patients show signs of TDP-43 protein loss

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