Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptome-pathology correlations predict CSNK1E-mediated TDP-43 phosphorylation in sporadic amyotrophic lateral sclerosis

ABSTRACT: Sporadic amyotrophic lateral sclerosis (sALS) is the most common (~90%) form of ALS. There are no animal models of sALS and exact molecular mechanisms remain elusive. Here, we elucidate gene-expression profiles in laser capture microdissected enriched surviving motor neurons (MNs) from sALS lumbar spinal cords in patients who had rostral onset and caudal progression. A strong signature was detected and immunological signals were computationally filtered. The filtered dataset showed clustering groups that were significantly explained by levels of phosphorylated TDP-43 (pTDP-43). Transcriptome-pathology correlations and enhanced crosslinking and immunoprecipitation combined with sequencing (eCLIP-seq) identified that Casein kinase 1ε (CSNK1E) had the highest correlation with pTDP-43 status and TDP-43 binding in its 3’UTR. Furthermore, CSNK1E interacted with TDP-43 on protein level and its overexpression lead to increased cytoplasmic pTDP-43 accumulations in iPSC-MNs, suggesting CSNK1E directly mediates TDP-43 phosphorylation. Therefore, we report an essential framework for molecular disease classification and transcriptome – pathology correlation in sALS to identify candidate genes for elucidating disease mechanisms and potential therapeutic interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103225 | GEO | 2018/06/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

TRAP-seq of spinal cord motor neurons from ALS diseased mice versus healthy mice

Project description:Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease featuring progressive loss of motor neuron (MN) function in the brain and spinal cord. Mutations in TARDBP, encoding the RNA-binding protein TDP-43, are one cause of ALS and TDP-43 mislocalization in MNs is a key pathological feature of >95% of ALS cases. While numerous studies support altered RNA regulation by TDP-43 as a major cause of disease, specific changes within MNs that trigger disease onset remain unclear. Here, we combined Translating Ribosome Affinity Purification (TRAP) with RNA sequencing to identify molecular changes in spinal MNs of TDP-43–driven ALS at motor symptom onset. By comparing the MN translatome of hTDP-43A315T mice to littermate controls and to mice expressing wildtype hTDP-43, we identify hundreds of mRNAs that were selectively up- or downregulated in MNs. We validated effects on Tex26, Syngr4, and Plekhb1 mRNAs in an independent TRAP experiment. Moreover, by quantitative immunostaining of spinal cord MNs we found corresponding protein level changes for SYNGR4 and PLEKHB1. We also observed these changes in spinal MNs of an independent ALS mouse model caused by a different patient mutant allele of TDP-43, suggesting that they may be a general feature of TDP-43-driven ALS. Thus, we have identified two new proteins deregulated in MNs at motor symptom onset in TDP-43-driven ALS models. This spatial and temporal pattern suggests that deregulation of these proteins could be functionally important for driving the transition to the symptomatic phase of disease.

2023-01-01 | GSE144640 | GEO

Homo sapiens

Project description:Transcriptome-pathology correlations predict CSNK1E-mediated TDP-43 phosphorylation in sporadic amyotrophic lateral sclerosis

| PRJNA400580 | ENA

Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS [terminally differentiated iPSC-derived astrocytes]

Project description:Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Herewe optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (>85%) functional populations of spinal cord MNs and ACs. We identifysignificantlyincreased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionallyidentify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay thatcould guide future therapeutic strategies in ALS.

2017-06-10 | GSE99843 | GEO

Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS

2017-05-31 | GSE98288 | GEO

Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration

Project description:Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.

2023-06-24 | GSE235312 | GEO

TDP-43 represses cryptic exon inclusion in FTD/ALS gene UNC13A

Project description:Through splicing analysis of a publicly available RNA-Seq dataset, we discovered TDP-43 represses a cryptic exon splicing event in UNC13A, a gene that had been associated with FTD/ALS through GWA studies. To confirm the sequences of the cryptic exons, we used shRNA to reduce TDP-43 levels in iPSC-derived motor neurons (iPSC-MNs) and by amplicon sequencing the RT-PCR product, we observed the insertion in cells with TDP-43 depletion but not in control shRNA-treated cells. Through sequence alignment, we verified the sequences of the cryptic exons.

2021-12-04 | GSE182976 | GEO

TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1

Project description:Accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43) is seen in both neurons and glia in a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Disease progression involves non-cell autonomous interactions among multiple cell types, including neurons, microglia and astrocytes. We investigated the effects in Drosophila of inducible, glial cell type-specific TDP-43 overexpression, a model that causes TDP-43 protein pathology including loss of nuclear TDP-43 and accumulation of cytoplasmic inclusions. We report that TDP-43 pathology in Drosophila is sufficient to cause progressive loss of each of the 5 glial sub-types. But the effects on organismal survival were most pronounced when TDP-43 pathology was induced in the perineural glia (PNG) or astrocytes. In the case of PNG, this effect is not attributable to loss of the glial population, because ablation of these glia by expression of pro-apoptotic reaper expression has relatively little impact on survival. To uncover underlying mechanisms, we used cell-type-specific nuclear RNA sequencing to characterize the transcriptional changes induced by pathological TDP-43 expression. We identified numerous glial cell-type specific transcriptional changes. Notably, SF2/SRSF1 levels were found to be decreased in both PNG and in astrocytes. We found that further knockdown of SF2/SRSF1 in either PNG or astrocytes lessens the detrimental effects of TDP-43 pathology on lifespan, but extends survival of the glial cells. Thus TDP-43 pathology in astrocytes or PNG causes systemic effects that shorten lifespan and SF2/SRSF1 knockdown rescues the loss of these glia, and also reduces their systemic toxicity to the organism.

2023-09-08 | GSE242209 | GEO

TDP-43-stratified single-cell proteomic profiling of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis

Project description:Single cell dataset of human motor neurons laser-captured from postmortem ALS and control tissues (1) ALS Pilot dataset (2) TDP43 stratified dataset Summary: Unbiased proteomics has been employed to interrogate central nervous system (CNS) tissues (brain, spinal cord) and fluid matrices (CSF, plasma) from amyotrophic lateral sclerosis (ALS) patients; yet, a limitation of conventional bulk tissue studies is that motor neuron (MN) proteome signals may be confounded by admixed non-MN proteins. Recent advances in trace sample proteomics have enabled quantitative protein abundance datasets from single human MNs (Cong et al., 2020b). In this study, we leveraged laser capture microdissection (LCM) and nanoPOTS (Zhu et al., 2018c) single-cell mass spectrometry (MS)-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control donor spinal cord tissues, leading to the identification of 2515 proteins across MNs samples (>900 per single MN) and quantitative comparison of 1870 proteins between disease groups. Furthermore, we studied the impact of enriching/stratifying MN proteome samples based on the presence and extent of immunoreactive, cytoplasmic TDP-43 inclusions, allowing identification of 3368 proteins across MNs samples and profiling of 2238 proteins across TDP-43 strata. We found extensive overlap in differential protein abundance profiles between MNs with or without obvious TDP-43 cytoplasmic inclusions that together point to early and sustained dysregulation of oxidative phosphorylation, mRNA splicing and translation, and retromer-mediated vesicular transport in ALS. Our data are the first unbiased quantification of single MN protein abundance changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein abundance changes in human neurologic diseases.

2023-06-07 | MSV000092119 | MassIVE

TDP-43 in ALS/FTLD studied by a novel aggregate extraction method

Project description:Accumulation of abnormally phosphorylated TDP-43 (pTDP-43) is the main pathological finding characterizing affected neurons in most patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). At least four different subtypes of FTLD-TDP have been described, based on the morphology and neuroanatomical distribution of pathological TDP-43 accumulations. To understand the molecular basis of this heterogeneity that correlates with clinical presentations, we developed SarkoSpin, a new method for the biochemical isolation of pathological TDP-43 from complex tissues. Using postmortem samples of 79 patients and controls, we show that SarkoSpin allows the physical separation of pTDP-43 from ~99.8% of total proteins, including the extreme bulk of physiological TDP-43. Pathological TDP-43 extracted from different disease subtypes forms large and buoyant assemblies of distinct densities and 3-dimentional shapes that correlate with specific neuropathological classifications.

2018-10-10 | PXD007873 | Pride

Nanopore sequencing of UNC13A from SHSY5Y and patient RNA

Project description:UNC13A contains a novel cryptic exon which is expressed upon TDP-43 knockdown. However, it also features TDP-43 regulated intron retention of a downstream intron. To investigate the correlation of these two events, we performed Nanopore sequencing of amplicons from SHSY5Y cells with inducible TDP-43 knockdown, and FTD patient RNA samples

2022-02-10 | E-MTAB-11244 | biostudies-arrayexpress

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