RNA-seq from USP10 and TDP-43 overexpression and TDP-43 knockdown associated with or without USP10 overexpression in HeLa cells
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PROVIDER: PRJEB97173 | ENA |
REPOSITORIES: ENA
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Project description:We performed RNA-seq on HeLa cells to assess the shared transcriptomics changes between USP10 and TDP-43 overexpression, as well as to understand the effect of USP10 overexpression on TDP-43 loss-of-function targets.
2025-09-21 | E-MTAB-15564 | biostudies-arrayexpress
Project description:Transactive response DNA-binding protein (TDP-43) plays a key pathological role in several neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the well-established role of TDP-43 in neurodegenerative disorders, it remains a complex area of study as it is unclear whether nuclear loss-of-function, cytoplasmic gain-of-function, or both drive pathogenesis. TDP-43 overexpression models are advantageous tools when developing drug candidates targeted at TDP-43, however, existing models often lack comprehensive RNA-seq data benchmarked against patient datasets. Given the value of TDP-43 overexpression as a model of ALS-related pathology, we have developed a stable, inducible system in a HEK293-derived cell line, offering a practical and scalable platform to investigate TDP-43 dysregulation. Utilizing this system, we found that TDP-43 overexpression reflected key features associated with ALS pathology, causing cytotoxicity, nucleocytoplasmic mislocalization, and extensive transcriptomic changes. Furthermore, comparative RNA-seq analysis between this model and ALS patient-derived data revealed substantial overlaps, where 64% of the differentially expressed genes in the TDP-43 overexpression cell line were also found to be altered in ALS patient tissue, supporting the disease relevance of the model. Genes of interest identified in the analysis included NUP85, SREBF2, VAMP5, WDR41, CDC23, DKC1, and PTS. This stable, inducible TDP-43 overexpression model and its associated transcriptomic dataset provide a versatile platform for ALS and other TDP-43 proteinopathy research, enabling the investigation of molecular drivers of TDP-43 dysfunction, the identification of potential disease-relevant pharmacological targets, and the evaluation of therapeutic candidates aimed at mitigating TDP-43 driven cytotoxicity or restoring normal TDP-43 localization.
2026-09-04 | GSE329332 | GEO
Project description:Neuronal TDP-43 aggregates are a hallmark ALS pathology. The integrated stress response (ISR) occurs downstream of TDP-43 pathology and may exacerbate TDP-43 aggregation and neurodegeneration. Here we tested the effects of overexpression of GFP-taggted TDP-43 proteins in H4 cells, in the presence or ascence of the EIF2B activiting small molecule DNL343. Cytoplasmic TDP-43 expression caused upregulation of ISR gene transcripts, including MTHFD2, GDF15, SLC7A11, and ATF3, relative to the GFP expressing sample. Transcript level changes induced by GFP-TDP-43(86-414) were prevented by DNL343 treatment, with significant downregulation of ISR genes, including CHAC1, ATF4, and DDIT3.
2025-06-30 | GSE281957 | GEO
Project description:Progranulin (GRN) mutations, which typically cause progranulin haploinsufficiency, cause frontotemporal dementia with TDP-43 pathology (FTD-TDP). It is not clear how progranulin insufficiency may cause FTD-TDP. Progranulin-insufficient mice develop FTD-related phenotypes without robust TDP-43 pathology, so we crossed crossed Grn+/- mice (RRID:MMRRC_036771-JAX) with transgenic mice expressing wild-type human TDP-43 (RRID:IMSR_JAX:012836) to investigate the effect of progranulin insufficiency on TDP-43 aggregation and TDP-43–related phenotypes.
2026-06-08 | GSE305500 | GEO
Project description:Cytoplasmic aggregation and nuclear depletion of TDP-43 are hallmarks of several age-related neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been a major challenge. Here, we produced amyloid-like fibrils from the recombinant low-complexity-domain of TDP-43, and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cell lines and iPSC-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin- and p62-accumulation, and recruit nuclear endogenous TDP-43 leading to nuclear-loss-of-function-driven disease-specific cryptic splicing defects. Cytoplasmic TDP-43 aggregates exhibit, with time, distinct heterogeneous morphologies as in patients including compacted, filamentous or fragmented, through the activation of cellular protein clearance pathways. Cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify templated aggregation of TDP-43 as a key mechanism driving both cytoplasmic gain- and nuclear-loss-of-function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.
2025-03-28 | GSE284828 | GEO
Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer. small RNA seq in SH-SY-5Y, SNB-19 and HT22 (TDP-43 siRNA VS Control siRNA)
2016-08-02 | E-GEOD-85065 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer.
2016-08-02 | GSE85065 | GEO
Project description:Discovery of proteins and pathways affected by overexpression of the protein TDP-43 in neurons cultured from wild-type and mice homogygous for the transgene.
2023-04-27 | PXD014889 | Pride
Project description:While predominantly nuclear localized in healthy cells, TDP-43 can transport between the nucleus and cytoplasm. In frontotemporal lobar degeneration (FTLD-TDP) and Amyotrophic Lateral Sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. However, a subset of patients develop nuclear aggregates. Expression of wild-type TDP-43 in C. elegans neurons results in nuclear protein accumulation and gain of function neuronal dysfunction. To enable comparative study of nuclear and cytoplasmic TDP-43 phenotypes, we generated new models with inactivating mutations in the nuclear localization sequence (NLS) of TDP-43. When compared to nuclear TDP-43 strains, similar protein levels of cytoplasmic TDP-43 caused less neuronal dysfunction in C. elegans. Using RNA sequencing, we found innate immune pathway increases in response to cytoplasmic but not nuclear TDP-43. We also found that overexpression of the unfolded protein response (UPR) transcription factor XBP-1s worsened outcomes for wild-type TDP-43 animals but improved TDP-43deltaNLS, suggesting different pathways controlling toxicity and clearance of nuclear versus cytoplasmic TDP-43. Taken together, this comparative approach supports a better understanding of human disease by allowing the study of cytoplasmic TDP-43 alongside nuclear TDP-43 models.
2026-08-05 | GSE326885 | GEO
Project description:The aim of this study is to understand the mechanisms of TDP-43 neurotoxicity. Here, we perform a RNA-Seq analysis in TDP-43 gain-of-fucntion (GOF) , TDP-43 loss-of-function and wild-type late pupae heads (73-90 hours APF) and perform TDP-43 GOF vs wild type and TDP-43 LOF vs wild-type differential expression analysis to show that both mechanisms presents defects in ecdysone receptor (ECR)-dependeint transcriptional program switching, and strongly deregulate expression from the neuronal microtubule associated protien Map205. RNA-seq was performed in two wild-type D.melanogaster biological replicates (Canton S, w1118 ), four biological replicates for TDP-43 (LOF) with two distinct genotypes (dTDP-43Δ142/Df(2R)106,dTDP-43Δ23/Δ142 ) and two TDP-43 GOF biological replicates (act5c>dTDP-43 ).
2013-01-22 | E-GEOD-42844 | biostudies-arrayexpress