ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
TDP-43 toxicity proceeds via calcium dysregulation and necrosis in aging Caenorhabditis elegans motor neurons.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 46 citations in OpenAlex.
- Distinct Transcriptional States of TDP-43 Pathology in an Alzheimer's Disease Mouse Model.Neuroscience bulletin · 2026Article
- TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.The FEBS journal · 2026Review
- Loss of CAMKK2 and iron-transport proteins-transferrin and its receptor-in the Alzheimer's disease hippocampus: link to tau pathology.Frontiers in cell and developmental biology · 2026Article
- TDP-43: unveiling the hidden key to cellular fate decisions.Cell communication and signaling : CCS · 2025Review
- SERCA Silencing Alleviates AßInternational journal of molecular sciences · 2025Article
- An ALS assembly modulator signature in peripheral blood mononuclear cells: implications for ALS pathophysiology, therapeutics, and diagnostics.Clinical proteomics · 2025Article
- Unraveling Molecular Targets for Neurodegenerative Diseases ThroughInternational journal of molecular sciences · 2025Review
- Article
- Article
- Simple models to understand complex disease: 10 years of progress fromFrontiers in neuroscience · 2023Review
- Aberrant neural activity in prefrontal pyramidal neurons lacking TDP-43 precedes neuron loss.Progress in neurobiology · 2022Article
- Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction.Antioxidants (Basel, Switzerland) · 2021Article
- Ryanodine Receptors: A Potential Treatment Target in Various Neurodegenerative Disease.Cellular and molecular neurobiology · 2021Review
- Caenorhabditis elegans for rare disease modeling and drug discovery: strategies and strengths.Disease models & mechanisms · 2021Review
- Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation.Scientific reports · 2020Article
- The Role of CaCells · 2020Review
- Review
- Neurotoxicity of polychlorinated biphenyls and related organohalogens.Acta neuropathologica · 2019Review
- Genetic analysis of KillerRed in C. elegans identifies a shared role of calcium genes in ROS-mediated neurodegeneration.Journal of neurogenetics · 2019Article
- Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases.International journal of molecular sciences · 2018Review
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Authors and funding
4 authors at 1 institution in 2 countries.
Funding
Abstract
Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with either sporadic or genetic origins characterized by the progressive degeneration of motor neurons. At the cellular level, ALS neurons show protein misfolding and aggregation phenotypes. Transactive response DNA-binding protein 43 (TDP-43) has recently been shown to be associated with ALS, but the early pathophysiological deficits causing impairment in motor function are unknown. Here we used Caenorhabditis elegans expressing mutant TDP-43(A315T) in motor neurons and explored the potential influences of calcium (Ca(2+)). Using chemical and genetic approaches to manipulate the release of endoplasmic reticulum (ER) Ca(2+)stores, we observed that the reduction of intracellular Ca(2+) ([Ca(2+)]i) rescued age-dependent paralysis and prevented the neurodegeneration of GABAergic motor neurons. Our data implicate elevated [Ca(2+)]i as a driver of TDP-43-mediated neuronal toxicity. Furthermore, we discovered that neuronal degeneration is independent of the executioner caspase CED-3, but instead requires the activity of the Ca(2+)-regulated calpain protease TRA-3, and the aspartyl protease ASP-4. Finally, chemically blocking protease activity protected against mutant TDP-43(A315T)-associated neuronal toxicity. This work both underscores the potential of the C. elegans system to identify key targets for therapeutic intervention and suggests that a focused effort to regulate ER Ca(2+) release and necrosis-like degeneration consequent to neuronal injury may be of clinical importance.
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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.