ArticleMolecular neurobiology2014
Disease-associated mutations of TDP-43 promote turnover of the protein through the proteasomal pathway.
Article in Molecular neurobiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 23 citations in OpenAlex.
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights.Biomedicines · 2025Review
- Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD.International journal of molecular sciences · 2022Review
- Optineurin Deficiency and Insufficiency Lead to Higher Microglial TDP-43 Protein Levels.International journal of molecular sciences · 2022Article
- Functional implication of ubiquitinating and deubiquitinating mechanisms in TDP-43 proteinopathies.Frontiers in cell and developmental biology · 2022Review
- Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging.Biomedicines · 2021Review
- Rapid in vitro quantification of TDP-43 and FUS mislocalisation for screening of gene variants implicated in frontotemporal dementia and amyotrophic lateral sclerosis.Scientific reports · 2021Article
- Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.Neurobiology of disease · 2021Review
- Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD.International journal of molecular sciences · 2021Review
- Proteotoxicity and Neurodegenerative Diseases.International journal of molecular sciences · 2020Review
- Why TDP-43? Why Not? Mechanisms of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis.Neuroscience insights · 2020Review
- Oxidized low-density lipoprotein inhibits the degradation of cyclophilin A via the lysosome in vascular smooth muscle cells.American journal of translational research · 2020Article
- TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response.PLoS genetics · 2019Article
- Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.Frontiers in molecular neuroscience · 2019Review
- Identification and characterization of ubiquitinylation sites in TAR DNA-binding protein of 43 kDa (TDP-43).The Journal of biological chemistry · 2018Article
- Causative Genes in Amyotrophic Lateral Sclerosis and Protein Degradation Pathways: a Link to Neurodegeneration.Molecular neurobiology · 2018Review
- Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum.Frontiers in molecular neuroscience · 2017Article
- Time-Point Dependent Activation of Autophagy and the UPS in SOD1G93A Mice Skeletal Muscle.PloS one · 2015Article
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Authors and funding
7 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
TAR DNA-binding protein (TDP-43) is a major component of most ubiquitin-positive neuronal and glial inclusions of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of missense mutations in the TARDBP gene have been identified in patients with familial and sporadic ALS, as well as familial FTLD with ALS. In the diseased states, TDP-43 proteins exhibit characteristic alterations, including truncation, abnormal phosphorylation, and altered subcellular distribution. However, the mechanisms by which TDP-43 mutations induce neurodegeneration remain unclear at present. In the current study, we analyzed protein turnover and subcellular distribution of wild-type TDP-43 and two disease-associated mutants (G298S and A382T) in human neuroblastoma SH-SY5Y cells stably expressing TDP-43 with a C-terminal tag. Cycloheximide chase experiments revealed more rapid turnover of TDP-43 mutant proteins than their wild-type counterpart. The decrease in the TDP-43 level after cycloheximide treatment was partially recovered upon co-treatment with the proteasome inhibitor, epoxomicin, but not the lysosomotropic agent, chloroquine, suggesting involvement of the proteasomal pathway in TDP-43 degradation. Analysis of the subcellular distribution of TDP-43 revealed predominant localization in the nuclear fraction, whereas the relative level in the cytoplasm remained unaltered in cells expressing either mutant protein, compared with wild-type protein. Our results suggest that higher turnover of disease-associated mutant TDP-43 proteins through the ubiquitin proteasome system is pathogenetically relevant and highlight the significance of proteolysis in the pathogenetic mechanism of TDP-43 proteinopathy.
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