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Abberant neuronal Wnt activation causes defective TDP43 localization

ABSTRACT: Abberant neuronal Wnt activation causes defective TDP43 localization

PROVIDER: PRJNA1032968 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26553100_1.fastq.gz	Fastqsanger.gz
	SRR26553100_2.fastq.gz	Fastqsanger.gz
	SRR26553101_1.fastq.gz	Fastqsanger.gz
	SRR26553101_2.fastq.gz	Fastqsanger.gz
	SRR26553102_1.fastq.gz	Fastqsanger.gz

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Abberant neuronal Wnt activation causes defective TDP43 localization

Project description:Conserved neuropathologies across multiple neurodegenerative diseases have identified shared causal pathways for neurodegeneration. One pathway involves the RNA-binding protein TDP-43, whose nuclear exclusion and cytoplasmic accumulation are established drivers of neurodegeneration. TDP-43 mislocalization is attributed to defective nucleocytoplasmic transport (NCT), but the underlying mechanisms are unclear. The vertebrate-specific six-transmembrane enzyme, Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5), cleaves the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. Here, we show that loss of GDE2 leads to aberrant sustained activation of canonical Wnt signaling in adult neurons, which is sufficient to cause NCT and nuclear pore abnormalities and the nuclear exclusion of TDP-43. GDE2 disruption coincides with TDP-43 nuclear exclusion in postmortem tissue from patients with Amyotrophic Lateral Sclerosis (ALS), and neuronal Wnt signaling is erroneously activated in Drosophila and induced human spinal neuronal (iSN) models of ALS. Wnt knockdown in Drosophila ALS models mitigates cell death, while pharmacological inhibition of Wnt activation in iSNs from ALS patients rescues mRNA levels of known TDP-43 splicing targets. Our study identifies GDE2 as a critical regulator of Wnt signaling in adult neurons and highlights Wnt pathway activation as a previously unappreciated mechanism contributing to NCT and TDP-43 abnormalities in disease.

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An intramolecular salt bridge linking TDP43’s RNA recognition motifs dictates RNA binding, protein stability and TDP43-dependent neurodegeneration

Project description:The majority of individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit neuronal cytoplasmic inclusions rich in the RNA binding protein TDP43. Even so, the relationship between TDP43’s RNA binding properties and neurodegeneration remain obscure. Here we show that engineered mutations disrupting a salt bridge between TDP43’s RNA recognition motifs interfere with nucleic acid binding and eliminate recognition of native TDP43 substrates. The accumulation of WT TDP43, but not RNA binding-deficient variants, disproportionately affected the abundance and splicing of encoding ribosome and oxidative phosphorylation components.

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Identifying microRNAs that bind to cytoplasmic TDP43

Project description:TDP43 is involved in microRNA biogenesis and found in cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS), and microRNAs are important for regulation of gene expression and represent potential biomarkers and therapeutic targets. Therefore, we examined microRNAs that preferentially bind cytoplasmic TDP43 using cellular models expressing TDP43 variants and NanoString miRNA profiling analyses. We identified cytoplasmic TDP43-associated miRNAs and predicted genes and pathways to gain insights into potentially relevant disease pathways, biomarkers, and reversible therapeutic targets for ALS.

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TDP43 proteinopathy exhibits disease, tissue, and context-specific cryptic splicing signatures

Project description:Mislocalization of the nuclear protein TDP43 is a hallmark of ALS and FTD and leads to de-repression and inclusion of cryptic exons, which represent promising biomarkers of TDP43 pathology. However, most cryptic exons to date have been identified from in vitro models, limiting our understanding of any tissue and/or cell-specific splices. We meta-analyzed published bulk RNA-Seq datasets representing 1,778 RNAseq profiles of ALS and FTD post mortem tissue, and in vitro models with experimentally depleted TDP43. We identified novel cryptic splices and mapped out their tissue-specificity, demonstrating subsets with distinct cortical and spinal cord enrichment. Novel events were validated by RNA-Seq and RT-qPCR in a new spinal cord cohort, and analysis of single-nucleus datasets localized cortical splices to layer-specific neuronal populations. This catalog of cryptic splices is the first step towards the development of biomarkers for cell type-specific TDP43 pathology.

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Project description:Colorectal cancer (CRC) arises from multi-step accumulation of genetic and epigenetic mutations that deregulate intestinal homeostasis leading to neoplastic transformation and metastases. Constitutive activation of WNT signaling is considered the initial driver oncogenic event to which CRCs remain addicted, also in their most aggressive metastatic forms. WNT activation provokes an aberrant signaling that converges into the nucleus where transcription and chromatin-remodeling factors cooperate to regulate cell identity. This leads to deregulated proliferation, block of differentiation and evasion from cell death pathways. We found that the protein arginine methyltransferase 1 (PRMT1) is synthetic lethal with WNT oncogenic activation in both genetically-defined mouse models and patient-derived metastatic CRC organoids. WNT activation regulates the subcellular localization of PRMT1, inducing its complete nuclear translocation. This makes CRCs specifically dependent on PRMT1 enzymatic activity to sustain WNT-dependent proliferation regardless of the mutational landscape carried by distinct patients. Together these data uncover a new molecular crosstalk between WNT activation and PRMT1 activity and place PRMT1 inhibition as a potential strategy to counteract CRC addiction to WNT oncogenic activation.

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Project description:In this study, we have investigated the molecular basis of Shh signalling during development of the secondary palate and how CNCC patterning and fate is influenced by the Shh signalling network. Using a gain-of-function mouse model to activate Smoothened (R26SmoM2) signalling in the palatal mesenchyme (Osr2-IresCre), we demonstrate ectopic Hh-Smo signalling results in fully penetrant cleft palate, disrupted oral-nasal patterning and defective palatine bone formation. We show that a series of Fox transcription factors, including the novel direct target Foxl1, function downstream of Hh signalling in the secondary palate. Furthermore, we demonstrate that Wnt/BMP antagonists, in particular Sostdc1, are positively regulated by Hh signalling, concomitant with down-regulation of key regulators of osteogenesis and BMP signalling effectors. Microarray analysis was performed on excised palatal shelves from Osr2-IresCre+/- (wild-type) and Osr2-IresCre;Smo+/M2 (mutant) embryos at embryonic day (E)13.5. Osr2-IresCre (PMID:17941042) and R26SmoM2 (PMID:15107405) mice have been described previously.

2018-10-02 | E-MTAB-5518 | biostudies-arrayexpress

Transcriptome analysis on TDP43 and SRSF3 downstream genes and binding RNAs in MDA-MB231 cells by Next Generation Sequencing

Project description:TDP43 and SRSF3 has been reported to be RNA-binding proteins; however their roles in breast cancer progression has not been examined previously. Here, we performed RNA-seq on MDA-MB231 cells stably expressed sh-control, shTDP43, shSRSF3 or sh-TDP43 and sh-SRSF3 using lentivirus in duplicates. In addition, MDA-MB231 cells with stable expression of flag-TDP43 or flag-SRSF3 were also generated by using lentivirus. RIP-seq was also applied to identify binding RNA against Flag antibodies.

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Identifying microRNAs that bind to cytoplasmic TDP43

Project description:Identifying microRNAs that bind to cytoplasmic TDP43

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LncRNA Malat1 inhibition of TDP43 cleavage suppresses IRF3-initiated antiviral innate immunity

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2020-06-10 | GSE134032 | GEO

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