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A Y374X TDP43 truncation leads to an altered fibroblast metabolic profile in amyotrophic lateral sclerosis driven by pyruvate and TCA cycle intermediate alterations

ABSTRACT: A Y374X TDP43 truncation leads to an altered fibroblast metabolic profile in amyotrophic lateral sclerosis driven by pyruvate and TCA cycle intermediate alterations

PROVIDER: PRJNA929957 | ENA |

REPOSITORIES: ENA

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A Y374X TDP43 truncation leads to an altered fibroblast metabolic profile in amyotrophic lateral sclerosis driven by pyruvate and TCA cycle intermediate alterations

Project description:Microarray and metabolomic analysis has been applied to the study of ALS in order to investigate how a Y374X TDP43 truncation mutation leads to an altered metabolic profile in fibroblasts driven by pyruvate and TCA cycle intermediate alterations The aim of the present study is to combine transcriptomics, metabolic flux analysis and protein expression analysis in fibroblasts in order to investigate how the Y34X truncation mutation in the TDP43 gene causes metabolic dysfunction

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A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations

Project description:A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.

| S-EPMC10213779 | biostudies-literature

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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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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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Project description:Pyruvate is a key metabolite in glycolysis and tricarboxylic acid (TCA) cycle. Exogenous pyruvate modulates metabolism, provides cellular protection, and is essential for the maintenance of human preimplantation embryos and human embryonic stem cells (hESCs). However, little is known about how pyruvate contributes to cell fate determination during epiblast stage. In this study, we used hESCs as a model to demonstrate that elevated exogenous pyruvate shifts metabolic balance towards oxidative phosphorylation in both maintenance and differentiation conditions. During differentiation, pyruvate potentiates mesoderm and endoderm lineage specification. Pyruvate production and its mitochondrial metabolism are required in BMP4-induced mesoderm differentiation. However, the TCA cycle metabolites do not have the same effect as pyruvate on differentiation. Further study shows that pyruvate increases AMP/ATP ratio, activates AMPK, and then modulates the mTOR pathway to enhance mesoderm differentiation. This study reveals that exogenous pyruvate not only controls metabolism, but also modulates signaling pathways in hESC differentiation.

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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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