Effects of overexpression of GFP-TDP-43, GFP-TDP-43(86-414) or GFP in human H4 cells, in the presence or absence of the EIF2B activator DNL343.
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PROVIDER: PRJNA1186324 | ENA |
REPOSITORIES: ENA
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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.
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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 assessed the effects of overexpression of a GFP-taggted C9orf72 repeat expansion in HEK293 cells on the transcriptome, in the presence or ascence of the EIF2B activiting small molecule DNL343. Expression of (G4C2)71-GFP upregulated most of the pre-defined ISR genes compared to GFP expression alone. These transcriptional changes were largely corrected by DNL343 treatment.
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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.
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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)
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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.
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Project description:Recent studies exploring the underlying pathomechanisms of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, have focused on biomolecular condensates, such as stress granules (SGs) and TDP-43 condensates. Our comprehension of the physicochemical processes that control the behavior of these condensates is still evolving. In this work, we reveal an unexpected function for YAP, a central component of the Hippo pathway, in regulating the dynamic behavior of SGs and TDP-43 condensates, a role that is independent of its transcriptional activity in Hippo pathway. We found that YAP can directly bind to the TB domain of TDP-43 through its N-terminal domain. This interaction promotes the homotypic multimerization and phase separation of TDP-43, while inhibiting its hyper- phosphorylation and solidification under stress conditions. Remarkably, YAP, whose mRNA level is reduced in ALS patients, is found to co-localize with pathological pTDP-43 aggregates in the cytoplasmic foci of ALS patient brains. Additionally, elevating YAP/Yorkie expression substantially reduces neurotoxicity in a TDP-43 transgenic fly model of ALS. Our findings highlight an unexpected chaperone-like role of YAP in managing ALS-associated biomolecular condensates, presenting significant implications for potential ALS treatments.
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Project description:TDP-43 is an important RNA binding protein. To better understand its binding targets in human neurons, we performed TDP-43 iCLIP on SHSY5Y cells.
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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.
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