ArticleThe Journal of biological chemistry2020
Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 44 citations in OpenAlex.
- Disruptions in RNA Splicing: A Key Regulator of Cognitive Impairment in Perioperative Neurocognitive Disorders.Neuroscience bulletin · 2026Review
- TDP-43-immunity-microbiota axis in amyotrophic lateral sclerosis: A potential pathogenic mechanism.Neural regeneration research · 2026Article
- TSC2 is a stress granule suppressor.bioRxiv : the preprint server for biology · 2026Article
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation.Biochemistry and biophysics reports · 2026Review
- Understanding liquid-liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation.Genome biology · 2026Review
- Aberrant NSUN1 activity connects mLife science alliance · 2026Article
- TRAF6 regulates ubiquitination-independent TDP-43 condensation and related neurodegeneration.Molecular psychiatry · 2025Article
- Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models.Life science alliance · 2025Article
- Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons.Nature communications · 2025Article
- Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.Cell · 2025Article
- Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.Cells · 2025Review
- TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation.bioRxiv : the preprint server for biology · 2025Article
- Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy.The Lancet. Neurology · 2025Review
- Nuclear pore dysfunction and disease: a complex opportunity.Nucleus (Austin, Tex.) · 2024Review
- Biomolecular condensates and disease pathogenesis.Science China. Life sciences · 2024Review
- Biophysical characterization of the phase separation of TDP-43 devoid of the C-terminal domain.Cellular & molecular biology letters · 2024Article
- The Role of Liquid-Liquid Phase Separation in the Accumulation of Pathological Proteins: New Perspectives on the Mechanism of Neurodegenerative Diseases.Aging and disease · 2024Review
- Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases.Molecular neurodegeneration · 2024Review
- Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.Molecular neurodegeneration · 2024Review
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Insoluble, hyperubiquitylated TAR DNA-binding protein of 43 kDa (TDP-43) in the central nervous system characterizes frontotemporal dementia and ALS in many individuals with these neurodegenerative diseases. The causes for neuropathological TDP-43 aggregation are unknown, but it has been suggested that stress granule (SG) formation is important in this process. Indeed, in human embryonic kidney HEK293E cells, various SG-forming conditions induced very strong TDP-43 ubiquitylation, insolubility, and reduced splicing activity. Osmotic stress-induced SG formation and TDP-43 ubiquitylation occurred rapidly and coincided with colocalization of TDP-43 and SG markers. Washout experiments confirmed the rapid dissolution of SGs, accompanied by normalization of TDP-43 ubiquitylation and solubility. Surprisingly, interference with the SG process using a protein kinase R-like endoplasmic reticulum kinase inhibitor (GSK2606414) or the translation blocker emetine did not prevent TDP-43 ubiquitylation and insolubility. Thus, parallel pathways may lead to pathological TDP-43 modifications independent of SG formation. Using a panel of kinase inhibitors targeting signaling pathways of the osmotic shock inducer sorbitol, we could largely rule out the stress-activated and extracellular signal-regulated protein kinase modules and glycogen synthase kinase 3β. For arsenite, but not for sorbitol, quenching oxidative stress with
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