Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Neurofilament accumulations in Amyotrophic Lateral Sclerosis patients’ motor neurons impair structural axonal initial segment integrity

ABSTRACT: Neurofilament (NF) accumulation is a pathological hallmark observed in motor neurons (MNs) of patients with Amyotrophic Lateral Sclerosis (ALS) and levels of NF in fluids is becoming the prime biomarker of ALS progression. However, the underlying mechanisms linking NF accumulations and MN degeneration are not elucidated. Here, we show that integrity of the axonal initial segment (AIS), the region of action potential initiation and of polarized trafficking, is impaired by NF accumulations in human MNs carrying mutations in the two main causal ALS genes: C9ORF72 and SOD1. We show that in mutant MNs derived from induced pluripotent stem cells, both light (NF-L) and phosphorylated heavy chains (pNF-H) accumulated progressively with MN aging and that pNF-H accumulation in the AIS region led to significant structural and molecular alterations. In parallel, ALS MNs acquired altered excitability with aging. Focusing on axonal organization appears as an effective readout for MN cell death and preserving AIS integrity could have important therapeutic implications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200474 | GEO | 2024/07/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Neurofilament accumulations in Amyotrophic Lateral Sclerosis patients’ motor neurons impair structural axonal initial segment integrity

Project description:Neurofilament accumulations in Amyotrophic Lateral Sclerosis patients’ motor neurons impair structural axonal initial segment integrity

| PRJNA824791 | ENA

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

Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS

Project description:Background: Astrocytes regulate neuronal function, synaptic formation and maintenance partly through secreted extracellular vesicles (EVs). In amyotrophic lateral sclerosis (ALS) astrocytes display a toxic phenotype that contributes to motor neuron (MN) degeneration. Methods: We used human induced astrocytes (iAstrocytes) from 3 ALS patients carrying C9orf72 mutations and 3 non-affected donors to investigate the role of astrocyte-derived EVs (ADEVs) in ALS astrocyte toxicity. ADEVs were isolated from iAstrocyte conditioned medium via ultracentrifugation and resuspended in fresh astrocyte medium before testing ADEV impact on HB9-GFP+ mouse motor neurons (Hb9-GFP+ MN). We used post-mortem brain and spinal cord tissue from 3 sporadic ALS and 3 non-ALS cases for PCR analysis. Findings: We report that EV formation and miRNA cargo are dysregulated in C9ORF72-ALS iAstrocytes and this affects neurite network maintenance and MN survival in vitro. In particular, we have identified downregulation of miR-494-3p, a negative regulator of semaphorin 3A (SEMA3A). We show here that by restoring miR-494-3p levels through expression of an engineered miRNA mimic we can downregulate Sema3A levels in MNs and increases MN survival in vitro. Consistently, we also report lower levels of mir-494-3p and higher levels of SEMA3A in cortico-spinal tract tissue isolated from sporadic ALS donors, thus demonstrating the pathological importance of this pathway in MNs and its therapeutic potential. Interpretation: ALS ADEVs and their miRNA cargo are involved in MN death in ALS and we have identified miR-494-3p as a potential therapeutic target.

2019-01-08 | GSE122640 | 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

FUS mutant human motoneurons transcriptome analysis reveals altered pathways and impairment of microRNA function

Project description:Mutations in the RNA-binding protein FUS have been genetically linked to Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease caused by the death of motoneurons (MNs). FUS is a ubiquitous protein and the mechanisms leading to selective MN loss downstream of FUS mutations are still largely unknown. We report the first transcriptome analysis of human purified MNs, obtained from isogenic induced Pluripotent Stem Cells (iPSCs) with a FUS wild-type or mutant genetic background. Gene ontology analysis of differentially expressed genes identified significant enrichment of pathways previously associated to other neurological diseases and non-FUS ALS, suggesting a common pathological mechanism. We also found several microRNAs deregulated in FUS mutant MNs and focused on miR-375 and miR-125b. Notably, miR-125b is a neural-enriched microRNA with multiple functions in the nervous system and miR-375 had been previously associated to MN survival. We report that relevant targets of both microRNAs, including the neural RNA-binding protein ELAVL4 and apoptosis factors such as p53, are aberrantly increased in FUS mutant MNs. Characterization of FUS RNA targets in the cell type primarily affected by the disease contributes to the definition of the pathogenic mechanisms of FUS-linked ALS.

2017-10-31 | GSE94888 | GEO

Cell autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS microglia contributes to neurodegeneration

Project description:The most common genetic mutation found in familial and sporadic amyotrophic lateral sclerosis (ALS), as well as fronto-temporal dementia (FTD), is a repeat expansion in the C9orf72 gene. C9orf72 is highly expressed in human myeloid cells, and although neuroinflammation and microglial pathology are widely found in ALS/FTD, the underlying mechanisms are poorly understood. Here, using human induced pluripotent stem cell-derived microglia-like cells (hiPSC-MG) harbouring C9orf72 mutation (mC9-MG) together with gene-corrected isogenic controls (isoC9-MG) and C9ORF72 knock-out hiPSC-MG (C9KO-MG), we show that reduced C9ORF72 protein is associated with impaired phagocytosis and an exaggerated inflammatory response upon stimulation with lipopolysaccharide, driven by sustained activation of NLRP3 inflammasome and NF-kB signalling. Analysis of the hiPSC-MG C9ORF72 interactome revealed an association of C9ORF72 with key regulators of autophagy, a process involved in the homeostatic regulation of the innate immune response. We found impaired initiation of autophagy in C9KO-MG and mC9-MG. Furthermore, through motor neuron-microglial (MN-MG) co-culture studies, we identified that autophagy deficit in mC9-MG led to increased vulnerability of C9 MNs to excitotoxic stimulus. Pharmacological activation of autophagy ameliorated the sustained activation of NLRP3 inflammasome and NF-B signalling, reversed the phagocytic deficit found in mC9-MG and also reduced MN death in MN-MG co-cultures. We validated these findings in blood-derived macrophages from people with C9orf72 mutation. Our results reveal an important role for C9ORF72 in regulating microglial immune homeostasis and identify dysregulation in human myeloid cells as a contributor to neurodegeneration in ALS/FTD

2023-03-02 | PXD032320 | Pride

Axonal transcriptome reveals upregulation of PLK1 as a protective mechanism in response to increased DNA damage in FUSP525L spinal motor neurons

Project description:Mutations in the gene fused-in-sarcoma (FUS) have been implicated in the motor neuron disease Amyotrophic lateral sclerosis (ALS). However, it is poorly understood how these gene mutations lead to selective motor neuron (MN) degeneration and if there are common pathomechanisms across disease etiology. To address the biological impact of the FUS-P525L mutation on the transcriptome of neurons, we applied RNA-sequencing (RNA-seq) method, using microfluidic chambers, to generate axonal as well as soma compartment specific profiles from isogenic induced pluripotent stem cells (iPSCs)-derived motor neurons. We demonstrate high purity of axonal and soma fractions, and further show that the axonal transcriptome is very specific from somas with fewer number of transcripts. Notably, functional enrichment analysis revealed a unique and distinct transcriptional landscape in both axonal and soma compartments including specific transcript types, most of which were required for RNA metabolism and DNA damage/cell cycle related processes, that were likely altered by FUS mutation. Among altered transcripts, we identified robust upregulation of polo-like kinase 1 (PLK1), a master regulator of cell cycle-related events, in FUS-P525L mutant MNs and confirmed that inhibition of PLK1 increases late apoptotic or necrosis-induced neuronal cell death in mutant neurons compared to healthy controls. Taken together, our findings provide insights into compartment-specific transcriptomics in FUS-ALS neuronal model and we propose that PLK1 activation is a consequence of MN-specific upregulation, possibly contributing to the DNA-damage response and other associated pathways including cell cycle and cytoskeleton machinery.

2024-09-10 | GSE276214 | GEO

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

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.

2017-05-31 | GSE98288 | GEO

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

2017-06-10 | GSE99843 | GEO

Expression data of iPSC-derived motor neurons from healthy donor, FALS, SALS, and drug-treated them

Project description:We established several iPSCs from healthy donors, familial ALS (FALS) patients, and sporadic ALS (SALS) patients. Using our differentiation protocol originally developed, we differentiated these iPSCs toward spinal motor neurons (MNs) and reproduced ALS pathology in a dish. In addition, we screened a drug candidate which suppressed the detected ALS-related phenotypes of these ALS models. For clarifying the molecular mechanisms of the ALS pathologies and the screened drug, we used microarrays to detail the global program of gene expression reflecting the MN pathology of FALS/SALS, and carefully compared with healthy donors and/or drug-treated ALS models based on their expression profiles.

2018-06-30 | GSE106382 | 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