Frontal cortex transcriptomic analysis of a TDP-43 Q331K knock-in mouse [20month]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA448283 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6924180_1.fastq.gz | Fastqsanger.gz | |||
| SRR6924180_2.fastq.gz | Fastqsanger.gz | |||
| SRR6924190_1.fastq.gz | Fastqsanger.gz | |||
| SRR6924190_2.fastq.gz | Fastqsanger.gz | |||
| SRR6924200_1.fastq.gz | Fastqsanger.gz |
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Project description:A key pathological feature of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) is the loss of nuclear localization and the accumulation of cytoplasmic inclusions of hyperphosphorylated TAR-DNA binding protein 43 (TDP-43). TDP-43 is a nucleic acid-binding protein involved in transcriptional repression, mRNA splicing, and the regulation of retrotransposable elements (RTEs) and endogenous retroviruses (ERVs). RTEs and ERVs are mobile genetic elements that constitute about 45% of our genome. These virus-like elements encode the capacity to replicate through an RNA intermediate and insert cDNA copies at de novo chromosomal locations. Their expression is a proven source of DNA damage and inflammatory signaling. Research in Drosophila has demonstrated a causal role of RTEs/ERVs in mediating both intracellular toxicity of TDP-43 and the intercellular spread of these toxic effects from glia to neurons. RTEs and ERVs are inappropriately expressed in postmortem tissues from ALS, FTD, and Alzheimer’s Disease (AD) patients, as well as in cell culture in response to TDP-43 disruption, suggesting that the findings in Drosophila may be conserved across species. But the role of RTEs and ERVs has not yet been examined in a vertebrate model of TDP-43 pathology. To investigate the functional contributions of RTEs in vertebrates, we utilized an established transgenic mouse model that overexpresses moderate levels of either human wild-type TDP-43 (hTDP-43-WT) or a mutant version with a specific causal amino acid substitution (hTDP-43-Q331K) associated with some inherited forms of the disease. Through RNA-sequencing of the motor cortex, and imaging of a LINE-1-EGFP retrotransposon indicator cassette, we found that the TDP-43 transgenic animals exhibit broad expression of RTEs and ERVs, along with replication of LINE-1 in glia and neurons in the motor cortex. This expression begins at the age of onset of neurological phenotypes, earlier in the hTDP-43-Q331K animals and much later in hTDP-43-WT. Although the motor defects progressively worsen over time, the LINE-1-EGFP replication reporter transiently labels spatially clustered groups of neurons and glia at the time of onset of motor symptoms. These EGFP-labeled neurons undergo cell death and are therefore lost over time. Unlabeled cells also die as a function of distance from the clusters of LINE-1-EGFP labeled neurons and glial cells. Together, these findings support the hypothesis that TDP-43 pathology triggers RTE/ERV expression in the motor cortex, that such expression marks cells for programmed cell death, with non-cell autonomous effects on nearby neurons and glial cells.
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Project description:No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell–derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.
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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: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 ).
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