ArticleJournal of cell science2014
Differential roles of the ubiquitin proteasome system and autophagy in the clearance of soluble and aggregated TDP-43 species.
Article in Journal of cell science, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 184 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
184 citing papers in PubMed, 1 synthesis or guideline pooled it, 266 citations in OpenAlex.
- Transcriptional targets of amyotrophic lateral sclerosis/frontotemporal dementia protein TDP-43 - meta-analysis and interactive graphical database.Disease models & mechanisms · 2022Pooled it
- LncRNAs LCETRL3 and LCETRL4 at chromosome 4q12 diminish EGFR-TKIs efficiency in NSCLC through stabilizing TDP43 and EIF2S1.Signal transduction and targeted therapy · 2022Trial
- The role of E3 ubiquitin ligases in selective types of macroautophagy.EMBO reports · 2026Review
- Distinct Transcriptional States of TDP-43 Pathology in an Alzheimer's Disease Mouse Model.Neuroscience bulletin · 2026Article
- Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.Signal transduction and targeted therapy · 2026Review
- Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.BMC medicine · 2026Review
- 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
- Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.The Journal of clinical investigation · 2026Review
- Review
- Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.The Journal of cell biology · 2026Article
- Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.BMB reports · 2026Review
- Ubiquitin Proteasome System Components, RAD23A and USP13, Modulate TDP-43 Solubility and Neuronal Toxicity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.International journal of molecular sciences · 2026Review
- Molecular Mechanisms and Therapeutic Potential of Degron-Mediated Proteostasis Regulation in Neurodegenerative Diseases.Cellular and molecular neurobiology · 2026Review
- Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.Frontiers in pharmacology · 2026Review
- Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model.Nature communications · 2025Article
- Article
- Shared and disease-specific pathways in frontotemporal dementia and Alzheimer's and Parkinson's diseases.Nature medicine · 2025Article
- C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.Acta neuropathologica communications · 2025Article
124 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
TAR DNA-binding protein (TDP-43, also known as TARDBP) is the major pathological protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Large TDP-43 aggregates that are decorated with degradation adaptor proteins are seen in the cytoplasm of remaining neurons in ALS and FTD patients post mortem. TDP-43 accumulation and ALS-linked mutations within degradation pathways implicate failed TDP-43 clearance as a primary disease mechanism. Here, we report the differing roles of the ubiquitin proteasome system (UPS) and autophagy in the clearance of TDP-43. We have investigated the effects of inhibitors of the UPS and autophagy on the degradation, localisation and mobility of soluble and insoluble TDP-43. We find that soluble TDP-43 is degraded primarily by the UPS, whereas the clearance of aggregated TDP-43 requires autophagy. Cellular macroaggregates, which recapitulate many of the pathological features of the aggregates in patients, are reversible when both the UPS and autophagy are functional. Their clearance involves the autophagic removal of oligomeric TDP-43. We speculate that, in addition to an age-related decline in pathway activity, a second hit in either the UPS or the autophagy pathway drives the accumulation of TDP-43 in ALS and FTD. Therapies for clearing excess TDP-43 should therefore target a combination of these pathways.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.