ArticleProceedings of the National Academy of Sciences of the United States of America2014
Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 122 papers.
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122 citing papers in PubMed, 190 citations in OpenAlex.
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Role of LXRβ in oligodendrocytes in neuronal survival.Molecular psychiatry · 2026Article
- Computational design of metalloproteases.bioRxiv : the preprint server for biology · 2025Article
- Loss of Nuclear TDP-43 Impairs Lipid Metabolism in Microglia-Like Cells.Research square · 2025Article
- Development of a targeted BioPROTAC degrader selective for misfolded SOD1.Nature communications · 2025Article
- Article
- Loss of Nuclear TDP-43 Impairs Lipid Metabolism in Microglia-Like Cells.bioRxiv : the preprint server for biology · 2025Article
- Critical impact of lysine 136 in TDP-43 phase separation, compartmentalization, and aggregation in living vertebrates.iScience · 2025Article
- Maintenance of neuronal TDP-43 expression requires axonal lysosome transport.bioRxiv : the preprint server for biology · 2025Article
- Inhibition of nonsense-mediated decay in TDP-43 deficient neurons reveals novel cryptic exons.bioRxiv : the preprint server for biology · 2025Article
- Challenges of modelling TDP-43 pathology in mice.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Review
- Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD.bioRxiv : the preprint server for biology · 2025Article
- Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Targeting Protein Aggregation in ALS.Biomolecules · 2024Review
- Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes.Brain : a journal of neurology · 2024Article
- Article
- The Biological Mechanisms and Clinical Roles of RNA-Binding Proteins in Cardiovascular Diseases.Biomolecules · 2024Review
- Elevated nuclear TDP-43 induces constitutive exon skipping.Molecular neurodegeneration · 2024Article
- Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons.iScience · 2024Article
- Restoring functional TDP-43 oligomers in ALS and laminopathic cellular models through baicalein-induced reconfiguration of TDP-43 aggregates.Scientific reports · 2024Article
62 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS.
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