ArticleeLife2025
Rapid and inducible mislocalization of endogenous TDP43 in a novel human model of amyotrophic lateral sclerosis.
Article in eLife, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.Journal of neurology · 2026Review
- Microglial Dysfunction Induced by C9ORF72 Dipeptide Repeat Proteins: Biomarker and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.Science (New York, N.Y.) · 2026Article
- The Gut Microbiome in Amyotrophic Lateral Sclerosis: Emerging Mechanisms and Therapeutic Potential.Molecular neurobiology · 2026Review
- Plasma isomiRs as Candidate Biomarkers for Amyotrophic Lateral Sclerosis.Neurology. Genetics · 2026Article
- Amyloidogenic oligomers derived from TDP-43 LCD promote the condensation and phosphorylation of TDP-43.Chemical science · 2026Article
- RNA Granules at the Crossroads of Synaptic Dysfunction and Neurodegeneration.Journal of neurochemistry · 2025Review
- Molecular Visualization of Neuronal TDP43 PathologybioRxiv : the preprint server for biology · 2025Article
- Article
- Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy.The Lancet. Neurology · 2025Review
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Authors and funding
6 authors.
Funding
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Abstract
Transactive response DNA binding protein 43 kDa (TDP43) proteinopathy, characterized by the mislocalization and aggregation of TDP43, is a hallmark of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). In this study, we describe the development of a new model of TDP43 proteinopathy using human induced pluripotent stem cell (iPSC)-derived neurons. Utilizing a genome engineering approach, we induced the mislocalization of endogenous TDP43 from the nucleus to the cytoplasm without mutating the TDP43 gene or using chemical stressors. Our model successfully recapitulates key early and late pathological features of TDP43 proteinopathy, including neuronal loss, reduced neurite complexity, and cytoplasmic accumulation and aggregation of TDP43. Concurrently, the loss of nuclear TDP43 leads to splicing defects, while its cytoplasmic gain adversely affects microRNA expression. Strikingly, our observations suggest that TDP43 is capable of sustaining its own mislocalization, thereby perpetuating and further aggravating the proteinopathy. This innovative model provides a valuable tool for the in-depth investigation of the consequences of TDP43 proteinopathy. It offers a clinically relevant platform that will accelerate the identification of potential therapeutic targets for the treatment of TDP43-associated neurodegenerative diseases, including sporadic ALS.
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