Noncoding RNAs induce TDP43 pathology in the ALS-iPSC models
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ABSTRACT:
PROVIDER: PRJNA783184 | ENA |
REPOSITORIES: ENA
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Project description:Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) degenerative disease with a major pathological feature of cytoplasmic TDP-43 aggregation. However, the mechanisms underlying TDP-43 proteinopathy are still largely unknown. We performed in vitro differentiation of ALS-induced pluripotent stem cells (ALS-iPSCs; carrying the TDP-43M337V mutation) and isogenic controls and found upregulation of paraspeckle-associated lncRNA NEAT1 isoforms in the ALS-iPSC-derived MNs (ALS-iPSC-MNs). Intriguingly, the upregulated NEAT1 isoforms were mislocalized to the cytoplasm of ALS-iPSC-MNs, and the cytoplasmic NEAT1 provoked TDP-43 and TDP-43M337V liquid-liquid phase separation, generating long-lived protein condensates. These condensates had reduced mobility and were converted into aggregates, finally co-aggregating with phospho-TDP-43. Disruption of NEAT1 expression reduced its cytoplasmic levels and also reduced the levels of TDP-43/TDP-43M337V condensates. In 3D neuromuscular organoids with the TDP-43M337V mutation, treatment with NEAT1-antisense oligonucleotides (NEAT1-ASO) promoted neuromuscular junction formation and function, as well as muscle contractility. Furthermore, treatment of TDP-43Q331K mice with Neat1-ASO attenuated TDP-43 pathology in spinal cord and preserved motor function. These findings suggest that NEAT1 plays an important role in TDP-43-associated pathology, and NEAT1-ASO may attenuate pathological TDP-43 aggregation to prevent motor neuron degeneration and muscle weakness in ALS.
2024-11-24 | GSE189470 | GEO
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.
2024-03-28 | GSE255683 | GEO
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.
2020-04-23 | GSE145214 | GEO
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.
2019-03-22 | GSE128647 | GEO
Project description:Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened TDP43 (sTDP43) splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.
| S-EPMC7269575 | biostudies-literature
Project description:Amyotrophic lateral sclerosis is the most common and fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 aggregates elicit immune responses remains underexplored. In this study, we demonstrate that TDP-43 aggregates are internalized by antigen presenting cell populations, cause vesicle rupture, and drive innate and adaptive immune cell activation by way of antigen presentation. Using a multiplex imaging platform, we observed enrichment of activated microglia/macrophages in ALS white matter that correlated with phosphorylated TDP-43 accumulation, CD8 T-cell infiltration, and major histocompatibility complex expression. Taken together, this study sheds light on a novel cellular response to TDP43 aggregates through an immunological lens.
2025-04-07 | GSE293662 | GEO
Project description:Amyotrophic lateral sclerosis is the most common and fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 aggregates elicit immune responses remains underexplored. In this study, we demonstrate that TDP-43 aggregates are internalized by antigen presenting cell populations, cause vesicle rupture, and drive innate and adaptive immune cell activation by way of antigen presentation. Using a multiplex imaging platform, we observed enrichment of activated microglia/macrophages in ALS white matter that correlated with phosphorylated TDP-43 accumulation, CD8 T-cell infiltration, and major histocompatibility complex expression. Taken together, this study sheds light on a novel cellular response to TDP43 aggregates through an immunological lens.
2025-04-08 | PXD062260 | Pride
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
2023-02-05 | GSE224138 | GEO
Project description:Aggregation of proteins under cellular stress plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and physiological consequences is poorly understood. We employed a general reporter to identify proteins forming aggregates under proteotoxic stress in human cells. Over 300 proteins were identified, forming different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule (SG) and a previously unknown solid inclusion containing components of the ER exit sites (ERES), such as SEC16A. TDP43 accumulation at ERES is antagonized by SG assembly, but enhanced by certain ALS-associated mutations. TDP43-ERES aggregation biases toward nascent TDP43 and, unlike SG, does not contain RNA. Such aggregation causes defects in ER-to-Golgi protein transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patient neurons.
2024-04-12 | PXD041480 | JPOST Repository
Project description:The role of glia in amyotrophic lateral sclerosis (ALS) is undeniable. Their disease-related activity has been extensively studied in the spinal cord, but only partly in the brain. We present herein a comprehensive study of glia in the motor cortex of SOD1(G93A) mice – a widely used model of ALS. Using single-cell RNA sequencing (scRNA-seq) and immunohistochemistry, we inspected astrocytes, microglia and oligodendrocytes, in four stages of the disease, respecting the factor of sex. We report insignificant motor neuron loss in the cortex, and likewise, minimal changes of glia throughout the disease progression and regardless of sex. Pseudobulk and single-cell analyses revealed subtle disease-related transcriptional alterations at the end-stage in microglia and oligodendrocytes, which were supported by immunohistochemistry. Therefore, our data conclusively prove that the SOD1(G93A) mouse motor cortex does not recapitulate the disease in patients, and we recommend the use of a different model for future studies of the cortical ALS pathology.
2023-04-21 | GSE206330 | GEO