ArticleEMBO reports2022
Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons.
Article in EMBO reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 39 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
39 citing papers in PubMed, 58 citations in OpenAlex.
- Structural Polymorphism of polyG Inclusions Revealed by In Situ Cryo-Electron Tomography.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- Toxic mechanisms of amyloid oligomers and therapeutic strategies.Protein science : a publication of the Protein Society · 2026Review
- From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.International journal of molecular sciences · 2026Review
- Reduction of RAD23A extends lifespan and mitigates pathology in a mouse model of TDP-43 proteinopathy.Nature communications · 2026Article
- Investigating the effect of progressive truncations at the ALS-linked protein TDP-43 RRM2 on its aggregation mechanism.Frontiers in molecular biosciences · 2026Article
- Icaritin ameliorates mitochondrial dysfunction and autophagy impairment in cellular models of Alzheimer's disease.Frontiers in aging neuroscience · 2026Article
- Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.bioRxiv : the preprint server for biology · 2025Article
- Blueprint of Collapse: Precision Biomarkers, Molecular Cascades, and the Engineered Decline of Fast-Progressing ALS.International journal of molecular sciences · 2025Review
- Molecular Visualization of Neuronal TDP43 PathologybioRxiv : the preprint server for biology · 2025Article
- RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.Molecular neurodegeneration · 2025Review
- Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights.Biomedicines · 2025Review
- Article
- Review
- Promoting proteostasis by cAMP/PKA and cGMP/PKG.Trends in molecular medicine · 2025Review
- The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.Journal of neural transmission (Vienna, Austria : 1996) · 2025Review
- Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Pathological Involvement of Protein Phase Separation and Aggregation in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Fundamental Aspects of Phase-Separated Biomolecular Condensates.Chemical reviews · 2024Review
- Proteotoxic stress and the ubiquitin proteasome system.Seminars in cell & developmental biology · 2024Review
Corrections and comments
- Erratum issued
Authors and funding
14 authors at 8 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aggregation of the multifunctional RNA-binding protein TDP-43 defines large subgroups of amyotrophic lateral sclerosis and frontotemporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C-terminal fragments of ~25 kDa ("TDP-25") accumulate in cytoplasmic inclusions. Here, we analyze gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics, and functional assays. In neurons, cytoplasmic TDP-25 inclusions are amorphous, and photobleaching experiments reveal gel-like biophysical properties that are less dynamic than nuclear TDP-43. Compared with full-length TDP-43, the TDP-25 interactome is depleted of low-complexity domain proteins. TDP-25 inclusions are enriched in 26S proteasomes adopting exclusively substrate-processing conformations, suggesting that inclusions sequester proteasomes, which are largely stalled and no longer undergo the cyclic conformational changes required for proteolytic activity. Reporter assays confirm that TDP-25 impairs proteostasis, and this inhibitory function is enhanced by ALS-causing TDP-43 mutations. These findings support a patho-physiological relevance of proteasome dysfunction in ALS/FTD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.