ArticleActa neuropathologica communications2019
Mice deficient in the C-terminal domain of TAR DNA-binding protein 43 develop age-dependent motor dysfunction associated with impaired Notch1-Akt signaling pathway.
Article in Acta neuropathologica communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 43 citations in OpenAlex.
- LncRNAs LCETRL3 and LCETRL4 at chromosome 4q12 diminish EGFR-TKIs efficiency in NSCLC through stabilizing TDP43 and EIF2S1.Signal transduction and targeted therapy · 2022Trial
- Challenges of modelling TDP-43 pathology in mice.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Review
- TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.Cell reports · 2025Article
- Peripheral proteinopathy in neurodegenerative diseases.Translational neurodegeneration · 2025Review
- Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment.Clinical drug investigation · 2024Review
- Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement.Scientific reports · 2024Article
- Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer's disease.Journal of neuroinflammation · 2024Article
- Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Importance of the Q/N-rich segment for protein stability of endogenous mouse TDP-43.Scientific reports · 2022Article
- Modelling amyotrophic lateral sclerosis in rodents.Nature reviews. Neuroscience · 2022Review
- Low-level overexpression of wild type TDP-43 causes late-onset, progressive neurodegeneration and paralysis in mice.PloS one · 2022Article
- Translational regulation in the brain by TDP-43 phase separation.The Journal of cell biology · 2021Article
- Review
- Identification of 11 candidate structured noncoding RNA motifs in humans by comparative genomics.BMC genomics · 2021Article
- Aggresome formation and liquid-liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43.Cell death & disease · 2020Article
- ALS-linked TDP-43Molecular brain · 2020Article
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Authors and funding
12 authors at 5 institutions in 2 countries.
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Abstract
Intracellular mislocalization of TAR DNA-binding protein 43 (TDP-43), a nuclear DNA/RNA-binding protein involved in RNA metabolism, is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Although the aggregation-prone, TDP-43 C-terminal domain is widely considered as a key component of TDP-43 pathology in ALS, recent studies including ours suggest that TDP-43 N-terminal fragments (TDP-∆C) may also contribute to the motor dysfunction in ALS. However, the specific pathological functions of TDP-43 N-terminal fragments in mice have not been elucidated. Here, we established TDP-∆C knock-in mice missing a part of exon 6 of murine Tardbp gene, which encodes the C-terminal region of TDP-43. Homozygous TDP-∆C mice showed embryonic lethality, indicating that the N-terminal domain of TDP-43 alone is not sufficient for normal development. In contrast, heterozygous TDP-∆C mice developed normally but exhibited age-dependent mild motor dysfunction with a loss of C-boutons, large cholinergic synaptic terminals on spinal α-motor neurons. TDP-∆C protein broadly perturbed gene expression in the spinal cords of aged heterozygous TDP-∆C mice, including downregulation of Notch1 mRNA. Moreover, the level of Notch1 mRNA was suppressed both by TDP-43 depletion and TDP-∆C expression in Neuro2a cells. Decreased Notch1 mRNA expression in aged TDP-∆C mice was associated with the age-dependent motor dysfunction and loss of Akt surviving signal. Our findings indicate that the N-terminal region of TDP-43 derived from TDP-∆C induces the age-dependent motor dysfunction associated with impaired Notch1-Akt axis in mice.
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