TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA523364 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12781800_1.fastq.gz | Fastqsanger.gz | |||
| SRR12781800_2.fastq.gz | Fastqsanger.gz | |||
| SRR12781797_1.fastq.gz | Fastqsanger.gz | |||
| SRR12781797_2.fastq.gz | Fastqsanger.gz | |||
| SRR12781798_1.fastq.gz | Fastqsanger.gz |
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Project description:When mutant superoxide dismutase 1 (SOD1) was first linked to amyotrophic lateral sclerosis (ALS), it was thought that ALS is a disease of oxidative stress, but this idea has taken a back seat since the discovery of multiple ALS-linked genes involved in RNA processing and proteostasis. Strikingly, a hallmark of both familial and sporadic ALS is the aggregation of the essential DNA/RNA binding protein TDP-43, which is thought to cause simultaneous loss-of-nuclear function and gain-of-cytoplasmic toxicity. A central unanswered question is what triggers ALS in adult followed by rapid and irreversible progression? Here we report that neuronal cells are particularly prone to oxidative stress to trigger TDP-43 aggregation, which in turn sponges a large subset of microRNAs and proteins, resulting in global mitochondrial imbalance that further elevates the oxidative stress. We propose that this ferocious cycle may underlie ALS onset and progression with oxidative stress as a key disease-driving event.
2020-10-12 | GSE126801 | GEO
Project description:When mutant superoxide dismutase 1 (SOD1) was first linked to amyotrophic lateral sclerosis (ALS), it was thought that ALS is a disease of oxidative stress. Since the discovery of multiple ALS-linked genes involved in RNA processing and proteostasis, most recent research has been focused on molecular defects induced by those mutant genes, but whether and how oxidative stress might contribute to magnification of those molecular defects have remained unaddressed. Strikingly, a hallmark of both familial and sporadic ALS is the aggregation of the essential DNA/RNA binding protein TDP-43, which is thought to cause simultaneous loss-of-nuclear function and gain-of-cytoplasmic toxicity. A central unanswered question is what triggers ALS in adult followed by rapid and irreversible progression? Here we report that neuronal cells are particularly prone to oxidative stress to trigger TDP-43 aggregation, which in turn sponges a large subset of microRNAs and proteins to cause both up-regulation and functional depletion of different sets of gene products. Remarkably, a large fraction of those functionally perturbed genes are nuclear genome-encoded mitochondrial proteins, thus resulting in a global mitochondrial imbalance, which further augments oxidative stress. We propose that this ferocious cycle driven by oxidative stress in combination with causal mutations in critical genes may underlie ALS onset and progression.
2020-11-20 | PXD021880 | Pride
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:Functional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in ~40% of FTLD cases, but the cascade of events leading to cell death are not understood. We have expressed human TDP-43 (hTDP-43) in Drosophila neurons and glia, a model that recapitulates many of the characteristics of TDP-43-linked human disease including protein aggregation pathology, locomotor impairment, and premature death. We report that such expression of hTDP-43 impairs small interfering RNA (siRNA) silencing, which is the major post-transcriptional mechanism of retrotransposable element (RTE) control in somatic tissue. This is accompanied by de-repression of a panel of both LINE and LTR families of RTEs, with somewhat different elements being active in glia vs neurons. hTDP-43 expression in glia causes an early and severe loss of control of a specific RTE, the endogenous retrovirus (ERV) gypsy. We demonstrate that gypsy causes the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial hTDP-43 either by genetically blocking expression of this RTE or by pharmacologically inhibiting RTE reverse transcriptase activity. Moreover, we provide evidence that activation of DNA damage-mediated programmed cell death underlies both neuronal and glial hTDP-43 toxicity, consistent with RTE-mediated effects in both cell types. Our findings suggest a novel mechanism in which RTE activity contributes to neurodegeneration in TDP-43-mediated diseases such as ALS and FTLD.
2017-02-15 | GSE85398 | GEO
Project description:Neurodegeneration in ALS and FTD results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43 seeding platform for quantitative, high-throughput assessment of TDP-43 aggregate uptake, cell-to-cell spreading and loss of function within living cells, while they progress towards pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized in human neuron-like cells, efficiently recruited endogenous TDP-43 and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. These neoaggregates progressively drove the nuclear egress of TDP-43 leading to its loss of function. Our model demonstrates the link between TDP-43 aggregation and aberrant cryptic splicing and provides new tools to identify genetic or pharmacologic modifiers of each step in the process.
2025-04-14 | PXD058981 | Pride
Project description:Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of ALS, occurring in over 97% of cases. A key consequence of TDP-43 nuclear loss is the de-repression of cryptic exons. Whilst TDP-43 regulated cryptic splicing is increasingly well catalogued, cryptic alternative polyadenylation (APA) events, which define the 3’ end of last exons, have been largely overlooked, especially when not associated with novel upstream splice junctions. We developed a bioinformatic pipeline to reliably identify distinct APA event types: alternative last exons (ALE), 3’UTR extensions (3’Ext) and ‘ composite ’ intronic polyadenylation (IPA) events. We identified novel neuronal cryptic APA sites induced by TDP-43 loss of function by systematically applying our pipeline to a compendium of publicly available and in house datasets. We find that TDP-43 binding sites and target motifs are enriched at these cryptic events and that TDP-43 can have both repressive and enhancing action on APA. Importantly, all categories of cryptic APA can also be identified in ALS and FTD post mortem brain regions with TDP-43 proteinopathy underlining their potential disease relevance. RNA-seq and Ribo-seq analyses indicate that distinct cryptic APA categories have different downstream effects on transcript and translation. Intriguingly, cryptic 3’Exts occur in multiple transcription factors, such as ELK1 , SIX3, and TLX1, and lead to an increase in RNA stability. 3’Exts are localised to the cytoplasm and neurites and translated leading to an increase in wild-type protein levels. In summary, we demonstrate that TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events and we expand the palette of TDP-43 loss consequences by showing this can also lead to an increase in normal protein translation.
2025-05-30 | GSE296716 | GEO
Project description:Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of ALS, occurring in over 97% of cases. A key consequence of TDP-43 nuclear loss is the de-repression of cryptic exons. Whilst TDP-43 regulated cryptic splicing is increasingly well catalogued, cryptic alternative polyadenylation (APA) events, which define the 3’ end of last exons, have been largely overlooked, especially when not associated with novel upstream splice junctions. We developed a bioinformatic pipeline to reliably identify distinct APA event types: alternative last exons (ALE), 3’UTR extensions (3’Ext) and ‘ composite ’ intronic polyadenylation (IPA) events. We identified novel neuronal cryptic APA sites induced by TDP-43 loss of function by systematically applying our pipeline to a compendium of publicly available and in house datasets. We find that TDP-43 binding sites and target motifs are enriched at these cryptic events and that TDP-43 can have both repressive and enhancing action on APA. Importantly, all categories of cryptic APA can also be identified in ALS and FTD post mortem brain regions with TDP-43 proteinopathy underlining their potential disease relevance. RNA-seq and Ribo-seq analyses indicate that distinct cryptic APA categories have different downstream effects on transcript and translation. Intriguingly, cryptic 3’Exts occur in multiple transcription factors, such as ELK1 , SIX3, and TLX1, and lead to an increase in RNA stability. 3’Exts are localised to the cytoplasm and neurites and translated leading to an increase in wild-type protein levels. In summary, we demonstrate that TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events and we expand the palette of TDP-43 loss consequences by showing this can also lead to an increase in normal protein translation.
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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.
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Project description:This SuperSeries is composed of the following subset Series: GSE40649: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (microarray) GSE40651: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (CLIP-Seq) GSE40652: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (RNA-Seq) Refer to individual Series
2012-09-30 | E-GEOD-40653 | biostudies-arrayexpress
Project description:Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of ALS, occurring in over 97% of cases. A key consequence of TDP-43 nuclear loss is the de-repression of cryptic exons. Whilst TDP-43 regulated cryptic splicing is increasingly well catalogued, cryptic alternative polyadenylation (APA) events, which define the 3’ end of last exons, have been largely overlooked, especially when not associated with novel upstream splice junctions. We developed a bioinformatic pipeline to reliably identify distinct APA event types: alternative last exons (ALE), 3’UTR extensions (3’Ext) and ‘ composite ’ intronic polyadenylation (IPA) events. We identified novel neuronal cryptic APA sites induced by TDP-43 loss of function by systematically applying our pipeline to a compendium of publicly available and in house datasets. We find that TDP-43 binding sites and target motifs are enriched at these cryptic events and that TDP-43 can have both repressive and enhancing action on APA. Importantly, all categories of cryptic APA can also be identified in ALS and FTD post mortem brain regions with TDP-43 proteinopathy underlining their potential disease relevance. RNA-seq and Ribo-seq analyses indicate that distinct cryptic APA categories have different downstream effects on transcript and translation. Intriguingly, cryptic 3’Exts occur in multiple transcription factors, such as ELK1 , SIX3, and TLX1, and lead to an increase in RNA stability. 3’Exts are localised to the cytoplasm and neurites and translated leading to an increase in wild-type protein levels. In summary, we demonstrate that TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events and we expand the palette of TDP-43 loss consequences by showing this can also lead to an increase in normal protein translation.
2025-05-30 | GSE296713 | GEO