Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Shared and distinct gain-of-function consequences from pathologic cytoplasmic versus nuclear TDP-43

ABSTRACT: While predominantly nuclear localized in healthy cells, TDP-43 can transport between the nucleus and cytoplasm. In frontotemporal lobar degeneration (FTLD-TDP) and Amyotrophic Lateral Sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. However, a subset of patients develop nuclear aggregates. Expression of wild-type TDP-43 in C. elegans neurons results in nuclear protein accumulation and gain of function neuronal dysfunction. To enable comparative study of nuclear and cytoplasmic TDP-43 phenotypes, we generated new models with inactivating mutations in the nuclear localization sequence (NLS) of TDP-43. When compared to nuclear TDP-43 strains, similar protein levels of cytoplasmic TDP-43 caused less neuronal dysfunction in C. elegans. Using RNA sequencing, we found innate immune pathway increases in response to cytoplasmic but not nuclear TDP-43. We also found that overexpression of the unfolded protein response (UPR) transcription factor XBP-1s worsened outcomes for wild-type TDP-43 animals but improved TDP-43deltaNLS, suggesting different pathways controlling toxicity and clearance of nuclear versus cytoplasmic TDP-43. Taken together, this comparative approach supports a better understanding of human disease by allowing the study of cytoplasmic TDP-43 alongside nuclear TDP-43 models.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE326885 | GEO | 2026/08/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Neuronal TDP-43 regulates myelin formation via neurexin 1 mRNA stabilization

Project description:TAR DNA-binding protein 43 (TDP-43) is a major pathological protein inextricably linked to Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Hypomyelination was detected in neuronal- specific TDP-43 knockout (TDP-43cKO) mice, and this impairment was recovered by the supplementation of cytoplasmic TDP-43 in neurons. We herein investigated the mechanisms that neuronal TDP-43 regulating neuron-oligodendrocyte interactions using the TDP-43cKO mice.

2026-02-09 | GSE246657 | 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

Expression Profiling of Caenorabditis elegans tdp-1 loss-of-function mutant

Project description:Transactive response DNA-binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein (hnRNP) with diverse activities, is a common denominator in several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Orthologs of TDP-43 exist from mammals to invertebrates, but their functions in lower organisms remain poorly understood. Here we systematically studied mutant Caenorhabditis elegans lacking the nematode TDP-43 ortholog, TDP-1. To understand the global gene expression regulation induced by the loss of tdp-1, the C. elegans transcriptomes were compared between the N2 WT animals and the tdp-1(ok803lf) mutant. Transcriptional profiling demonstrated that the loss of TDP-1 altered expression of genes functioning in RNA processing and protein folding. These results suggest that the C. elegans TDP-1 as an RNA-processing protein may have a role in the regulation of protein homeostasis and aging. Global gene expression profiling was performed to compare the transcriptome of wild-type (N2) Caenorabditis elegans and that of tdp-1(ok803) loss-of-function mutant. We analyzed mixed stages of Caenorabditis elegans, wild-type N2 versus tdp-1(ok803), using the Affymetrix C. elegans genome array. Three biological replicates were performed.

2012-02-21 | E-GEOD-34113 | biostudies-arrayexpress

A TDP-43 acetylation-mimic mutation that disrupts RNA-binding drives FTLD-like neurodegeneration in a mouse model of sporadic TDP-43 proteinopathy

Project description:TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs its RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of aberrant acetylation-mimic TDP-43K145Q resulted in stress-induced phase-separated nuclear TDP-43 foci formation and loss-of-TDP-43-function in mouse primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons. Aged mice harboring the single TDP-43K145Q mutation recapitulate several key hallmarks of neurodegenerative proteinopathies, including progressive TDP-43 phosphorylation and insolubility, cytoplasmic mis-localization, widespread transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which aberrant TDP-43 acetylation drives neuronal dysfunction and cognitive decline through alternative splicing and transcription of genes important in synaptic plasticity and apoptosis, providing a new paradigm to interrogate FTLD disease mechanisms and uncover disease-modifying therapeutics.

2023-01-09 | GSE216294 | GEO

Expression Profiling of Caenorabditis elegans tdp-1 loss-of-function mutant

2012-02-21 | GSE34113 | GEO

TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons - Surface labelling

Project description:Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43 knockdown neurons and decreased 2-transferrin levels in patient CSF. Whole proteome quantification identified upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase report assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed broad reduction in surface expression of key receptors upon TDP-43 knockdown including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43 induced neurodegeneration by blocking trophic signaling.

2016-09-29 | PXD004744 | Pride

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated disease

Project description:Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD and developed a complementary open-access webtool, TDP-map (https://shiny.rcc.uq.edu.au/TDP-map/). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in disease.

2024-01-31 | PXD042382 | Pride

Alterations in single-cell transcriptomic levels and cellular localisation of hnRNP proteins in Frontotemporal Lobar Degeneration

Project description:Frontotemporal dementia (FTD) is a neurodegenerative disorder with a strong heritable component. Frontotemporal lobar degeneration (FTLD) refers to the pathological changes seen in FTD, characterised by atrophy of the frontal and temporal lobes and the presence of abnormal protein inclusions. In the case of FTLD with hyperphosphorylated TDP-43 positive inclusions (FTLD-TDP), five pathological subtypes (A, B, C, D, and E) are observed based on the types and distribution of inclusions found in the brain. In all subtypes, there tends to be a large variability in the amount of pathological inclusions observed between cases, with limited correlation to clinical manifestations. TDP-43 is an RNA binding protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family which along with other hnRNPs modulates multiple aspects of RNA processing. HnRNPs other than TDP-43 have been implicated in several neurological diseases, including ALS, FTLD-TDP, FTLD-FUS and Alzheimer's disease. Multiple hnRNPs have been found in pathological inclusions in specific subtypes of FTLD-TDP, suggesting potential roles in the disease process. The role of the hnRNP network in FTLD disease pathogenesis has not yet been investigated. This study aimed to comprehensively evaluate the presence and expression of hnRNP proteins in two pathological subtypes of sporadic FTLD-TDP (A and C) as well as the genetic form FTLD-TDP A C9orf72 using immunohistochemistry and gene expression analysis by single cell RNA-sequencing. We sought to determine whether hnRNPs exhibited aberrant expression at the protein and transcript level in FTLD cases with TDP-43 pathology.

2026-03-02 | GSE288106 | GEO

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

Project description: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.

2023-12-21 | GSE117873 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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