Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

TDP-43 is a genome-wide DNA-binding protein and regulator of snRNA expression

ABSTRACT: TAR DNA-binding protein 43 (TDP-43) is the major protein component of neuronal inclusions characterizing the adult-onset neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Whereas TDP-43 was originally identified as a DNA-binding protein that bound the HIV-1 trans-activation response (TAR) DNA element, recent work elucidating its role in neurodegenerative disease pathogenesis has largely focused on TDP-43’s role as an RNA-binding protein. Here, we demonstrate that in human cells, TDP-43 binds DNA genome-wide, with strong enrichment at small nuclear RNA (snRNA) genes. Moreover, TDP-43 binding to snRNA genes is not dependent on RNA, and the snRNA products of TDP-43-bound sites are incorporated into Smith antigen-containing snRNPs. Furthermore, TDP-43 knockdown increases expression of bound snRNA genes, supporting a role for TDP-43 in the negative regulation of snRNA biogenesis. Finally, ALS-associated missense mutations in the gene encoding TDP-43, TARDBP, reduce binding to snRNA genes. Together, our data suggest that the DNA-binding role of TDP-43 is important in health and in disease, and aberrant TDP-43 binding to snRNA gene loci may alter splicing function in ALS and FTLD-TDP.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117873 | GEO | 2023/12/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia

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.

2020-10-20 | GSE153960 | GEO

RNA sequencing of mice expressing NLS-hTDP-43

Project description:TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display a loss of endogenous mouse nuclear TDP-43 as well as dramatic changes in gene expression as measured by microarray. Here, we analyze RNA-sequencing data from the ∆NLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice and High Throughput Sequencing of RNA isolated by CrossLinking ImmunoPrecipitation (HITS-CLIP) data of TDP-43’s RNA binding targets to further investigate the dysregulation of gene expression in the ∆NLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3’ untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.

2015-10-15 | GSE65973 | GEO

The gene expression analysis of TDP knocked down MIN6 cells.

Project description:TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS). Here, we show that ALS subjects have reduced early-phase insulin secretion and that the nuclear localization of TDP-43 is lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibits exocytosis, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6). Using microarray analysis, we identified the genes causing insulin impaired in TDP knocked down MIN6 cells.

2019-01-23 | GSE125424 | GEO

TAF15 amyloid filaments in neurodegenerative disease

Project description:Frontotemporal dementia (FTD) is the most common form of dementia after Alzheimer's disease and results from frontotemporal lobar degeneration (FTLD). The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins1. In the majority of cases, the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterising different FTLD subtypes2,3. The presence, identities and structures of amyloid filaments in the remaining ~10% of FTLD cases are unknown, but are widely believed to be composed of the protein fused in sarcoma (FUS). As such, these cases are commonly referred to as FTLD-FUS. Here, we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Unexpectedly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15), rather than of FUS itself. The filament fold is formed from residues 7 to 99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, who also showed changes associated with amyotrophic lateral sclerosis (ALS), suggesting that TAF15 proteinopathy may underlie a disease spectrum of FTLD and ALS. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.

2023-12-07 | PXD044821 | Pride

Retrotransposon Activation Contributes to Neurodegeneration in a Drosophila TDP-43 Model of ALS

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

Neuronal VCP loss of function recapitulates FTLD-TDP pathology

Project description:The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivated VCP in murine postnatal forebrain neurons (VCP cKO). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulated features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.

2021-06-16 | GSE178257 | GEO

Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport

Project description:Transactive response DNA-binding protein 43 (TDP-43) is a predominantly nuclear, ubiquitously expressed RNA and DNA-binding protein. It recognises and binds to UG repeats and is involved in pre-mRNA splicing, mRNA stability and microRNA metabolism. TDP-43 is essential in early embryonic development but accumulates in cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal lobar degeneration (FTLD). It is not known yet whether cytoplasmic aggregates of TDP-43 are toxic or protective but they are often associated with a loss of TDP-43 from the nucleus and neurodegeneration may be caused by a loss of normal TDP-43 function or a gain of toxic function. Here we present a proteomic study to analyse the effect of loss of TDP-43 on the proteome. Our results indicate that TDP-43 is an important regulator of RNA metabolism and intracellular transport. We show that Ran-binding protein 1 (RanBP1), DNA methyltransferase 3 alpha (Dnmt3a) and chromogranin B (CgB) are downregulated upon TDP-43 knockdown. Subsequently, transportin 1 level is increased as a result of RanBP1 depletion. Improper regulation of these proteins and the subsequent disruption of cellular processes may play a role in the pathogenesis of the TDP-43 proteinopathies ALS and FTLD.

2015-06-29 | PXD001668 | Pride

Distinguishing post-translational modifications in dominantly inherited FTD: FTLD-TDP Type A (GRN) versus Type B (C9orf72)

Project description:Frontotemporal dementias are neuropathologically characterized by frontotemporal lobar degeneration (FTLD). Intraneuronal inclusions of transactive response DNA-binding protein 43 kDa (TDP-43) are the defining pathologic hallmark of approximately half of the FTLD cases, being referred to as FTLD-TDP. The classification of FTLD-TDP into five subtypes (Type A to Type E) is based on pathologic phenotypes; however, the molecular determinants underpinning the phenotypic heterogeneity of FTLD-TDP are not well known. It is currently undetermined whether TDP-43 post-translational modifications (PTMs) may be related to the phenotypic diversity of the FTLDs. Thus, the investigation of FTLD-TDP Type A and Type B, associated with GRN and C9orf72 mutations, becomes an essential step. Immunohistochemistry was used to identify and map the intraneuronal inclusions. Sarkosyl-insoluble TDP-43 was extracted from brains of GRN and C9orf72 carriers post-mortem and studied by western blot analysis, immunoelectron microscopy and mass spectrometry. Filaments of TDP-43 were present in all FTLD-TDP preparations. PTM profiling identified multiple phosphorylated, N-terminal acetylated, or otherwise modified residues, several of which have been identified for the first time as related to sarkosyl-insoluble TDP-43. Several PTMs were specific for either Type A or Type B, while others were identified in both types. The current results provide evidence that the intraneuronal inclusions in the two genetic diseases contain TDP-43 filaments. The discovery of novel, potentially Type-specific TDP-43 PTMs emphasizes the need to determine the mechanisms leading to filament formation and PTMs, and the necessity of exploring the validity and occupancy of PTMs in a prognostic/diagnostic setting.

2022-04-12 | MSV000089242 | MassIVE

Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms

Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here, we show that nano-size polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. Additionally, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing TDP-43’s condensation and solidification. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.

2024-04-19 | GSE264018 | GEO

Analysis of accumulated TDP-43 in neurodegenerative disease brain

Project description:The abnormal aggregation of transactive response DNA-binding protein of 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD).

2021-10-08 | PXD029001 | JPOST Repository

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data