ArticlePloS one2015
Transcriptomic Changes Due to Cytoplasmic TDP-43 Expression Reveal Dysregulation of Histone Transcripts and Nuclear Chromatin.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
- Transcriptional targets of amyotrophic lateral sclerosis/frontotemporal dementia protein TDP-43 - meta-analysis and interactive graphical database.Disease models & mechanisms · 2022Pooled it
- RNArchitects: how hnRNPs shape neuronal landscapes.Brain : a journal of neurology · 2026Review
- Single-nucleus transcriptome atlas of orbitofrontal cortex in ALS with a deep learning-based decoding of alternative polyadenylation mechanisms.Cell genomics · 2025Article
- Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration.Molecular neurodegeneration · 2025Review
- Alternative 3' UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD.Molecular brain · 2025Article
- Decoding TDP-43: the molecular chameleon of neurodegenerative diseases.Acta neuropathologica communications · 2024Review
- Histone post-translational modification and heterochromatin alterations in neurodegeneration: revealing novel disease pathways and potential therapeutics.Frontiers in molecular neuroscience · 2024Review
- TDP-43 Epigenetic Facets and Their Neurodegenerative Implications.International journal of molecular sciences · 2023Review
- Article
- Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD.International journal of molecular sciences · 2022Review
- SMN controls neuromuscular junction integrity through U7 snRNP.Cell reports · 2022Article
- Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis.Acta neuropathologica · 2022Article
- Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Review
- Hippocampal neurobiology and function in an aged mouse model of TDP-43 proteinopathy in an APP/PSEN1 background.Neuroscience letters · 2021Article
- Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3.eLife · 2020Article
- The role of TDP-43 mislocalization in amyotrophic lateral sclerosis.Molecular neurodegeneration · 2020Review
- Risk Factors and Emerging Therapies in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2019Review
- Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons.Cell reports · 2019Article
- Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.Frontiers in molecular neuroscience · 2019Review
- The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology.Molecular and cellular biology · 2018Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking, and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display dramatic changes in gene expression as measured by microarray, suggesting that cytoplasmic TDP-43 may be associated with a toxic gain-of-function. Here, we analyze new RNA-sequencing data from the ΔNLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice to investigate further the dysregulation of gene expression in the ΔNLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3' untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.
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