ArticleThe Journal of biological chemistry2011
TDP-43-induced death is associated with altered regulation of BIM and Bcl-xL and attenuated by caspase-mediated TDP-43 cleavage.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers, 1 of them a synthesis that pooled it.
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Who cites it
61 citing papers in PubMed, 1 synthesis or guideline pooled it, 112 citations in OpenAlex.
- A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.NPJ systems biology and applications · 2025Pooled it
- Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.The Journal of clinical investigation · 2026Review
- Inhibiting Glycogen Synthase Kinase 3 Suppresses TDP-43-Mediated Neurotoxicity in a Caspase-Dependent Manner.Molecular neurobiology · 2026Article
- The mechanisms underlying TDP-43-associated neurodegeneration in Alzheimer's disease and related dementias.Molecular psychiatry · 2025Review
- Article
- Frontotemporal-TDP and LATE Neurocognitive Disorders: A Pathophysiological and Genetic Approach.Brain sciences · 2023Review
- Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates.Microbial cell (Graz, Austria) · 2023Article
- Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis.Frontiers in aging neuroscience · 2023Review
- Modulation of assembly of TDP-43 low-complexity domain by heparin: From droplets to amyloid fibrils.Biophysical journal · 2022Article
- The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases.International journal of molecular sciences · 2022Review
- Effects of intracellular calcium accumulation on proteins encoded by the major genes underlying amyotrophic lateral sclerosis.Scientific reports · 2022Article
- Towards Understanding the Relationship Between ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis.Frontiers in aging neuroscience · 2022Review
- The Role of Extracellular Matrix Components in the Spreading of Pathological Protein Aggregates.Frontiers in cellular neuroscience · 2022Review
- Review
- The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS.Antioxidants (Basel, Switzerland) · 2021Review
- Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies.Biomedicines · 2021Review
- TDP-43 and ER Stress in Neurodegeneration: Friends or Foes?Frontiers in molecular neuroscience · 2021Review
- The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS.Frontiers in cellular neuroscience · 2021Review
- Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress.Cellular and molecular life sciences : CMLS · 2020Article
- The role of TDP-43 mislocalization in amyotrophic lateral sclerosis.Molecular neurodegeneration · 2020Review
1 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Abnormal aggregates of transactive response DNA-binding protein-43 (TDP-43) and its hyperphosphorylated and N-terminal truncated C-terminal fragments (CTFs) are deposited as major components of ubiquitinated inclusions in most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). The mechanism underlying the contribution of TDP-43 to the pathogenesis of these neurodegenerative diseases remains unknown. In this study, we found that a 2-5-fold increase in TDP-43 expression over the endogenous level induced death of NSC34 motor neuronal cells and primary cortical neurons. TDP-43-induced death is associated with up-regulation of Bim expression and down-regulation of Bcl-xL expression. siRNA-mediated reduction of Bim expression attenuates TDP-43-induced death. Accumulated evidence indicates that caspases are activated in neurons of ALS and FTLD-U patients, and activated caspase-mediated cleavage of TDP-43 generates CTFs of TDP-43. Here, we further found that the ER (endoplasmic reticulum) stress- or staurosporine-mediated activation of caspases leads to cleavage of TDP-43 at Asp(89) and Asp(169), generating CTF35 (TDP-43-(90-414)) and CTF27 (TDP-43-(170-414)) in cultured neuronal cells. In contrast to TDP-43, CTF27 is unable to induce death while it forms aggregates. CTF35 was weaker than full-length TDP-43 in inducing death. A cleavage-resistant mutant of TDP-43 (TDP-43-D89E/D169E) showed stronger death-inducing activity than wild-type TDP-43. These results suggest that disease-related activation of caspases may attenuate TDP-43-induced toxicity by promoting TDP-43 cleavage.
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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.