Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB
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ABSTRACT:
PROVIDER: PRJNA1195017 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31636800_1.fastq.gz | Fastqsanger.gz | |||
| SRR31636800_2.fastq.gz | Fastqsanger.gz | |||
| SRR31636900_1.fastq.gz | Fastqsanger.gz | |||
| SRR31636900_2.fastq.gz | Fastqsanger.gz | |||
| SRR31637000_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Microglia play crucial roles in mediating neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS). However, the role of microglia in ALS remains incompletely understood. Methods: Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes. Results: Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes. Conclusions: VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from ALS models and post mortem tissue and are independent of GPNMB. VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.
2024-12-09 | GSE282665 | GEO
Project description:Microglia play crucial roles in mediating neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS). However, the role of microglia in ALS remains incompletely understood. Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes. Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes. VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from ALS models and post mortem tissue and are independent of GPNMB. VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.
2025-05-07 | PXD057586 | Pride
Project description:BackgroundMicroglia play crucial roles in maintaining neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia in ALS/FTD remains incompletely understood.MethodsHere, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes.ResultsTranscriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with the inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes.ConclusionsVCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from other ALS models and post mortem tissue. These phenotypes occur independently of GPNMB. Additionally, VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.
| S-EPMC11590569 | biostudies-literature
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
Project description:Dominant mutations in unrelated genes cause fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and include VCP, which is associated with multisystem proteinopathy (MSP). Conditional inactivation of VCP in postnatal forebrain neurons (VCP cKO) caused cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, TDP-43 inclusions and hyperactivity. Quantitative proteomics and single nuclei RNA sequencing on VCP cKO brains identified synaptogenesis and the unfolded protein response as the most decreased and increased pathways respectively. Conditional expression of a single MSP disease mutation, VCP-R155C, in cortical neurons similarly recapitulated features of VCP inactivation and FTLD-TDP. Comparison of transcriptomic and proteomic datasets from genetically defined FTD patients revealed that profiles from GRN carriers were similar to VCP insufficiency. These data support a deficiency in VCP dependent functions as the pathogenic mechanism of FTLD-TDP and reveal an unexpected pathogenic similarity with progranulin deficiency. Enhancing VCP function may be therapeutic in MSP and related forms of FTLD-TDP.
2021-08-06 | PXD026685 | Pride
Project description:Currently, both reliable biomarkers for disease monitoring and specific therapeutic targets are needed to combat atherosclerosis, one of the dangerous lipid metabolism disorders. We observed attenuation of atherosclerosis in a GPNMB auto-mutant (GpnmbR150X) mouse model as well as in a myeloid-specific Gpnmb-knockout mouse model. Furthermore, in GpnmbR150X BMDMs, we observed that impaired lipid droplet formation, enhanced lipid oxidative metabolism, and more robust lipid degradation by the lysosomal pathway suppressed the macrophage foaming, thereby reducing the atherosclerotic burden of excess OxLDL.
2025-09-04 | GSE274954 | GEO
Project description:Gaucher disease (GD) is characterized by the presence of glucosylceramide-laden macrophages (Gaucher cells) as the result of deficiency in the lysosomal hydrolase glucocerebrosidase (GBA). Non-neuronopathic type 1 GD is effectively treated by infusions with macrophage-targeted recombinant glucocerebrosidase. We here report how LC-MSE analysis of the proteome of laser-dissected splenic Gaucher cells revealed high expression of several proteins amongst which was gpNMB. This was confirmed by histochemistry and RNA quantification. Macrophages produce gpNMB as membrane protein but release soluble fragments. In plasma of symptomatic Gaucher patients (n=59) soluble gpNMB was next found to be on average 25-fold increased prior to treatment, without overlap with control values, (control mean: 20 ng/ml; range 11-34 ng/ml vs. GD mean: 495 ng/ml; range: 137-1283 ng/ml).
2016-09-27 | PXD001598 | Pride
Project description:Study of the effects of the VCP knockdown. VCP (p97, yeast cdc48) is a hexameric AAA ATPase involved in various cellular functions including degradation of proteins by the ubiquitin-proteasome system. We examine the consequences of the reduction of VCP levels after RNAi of VCP in HeLa cells. We find ~30 transcripts upregulated in a sequence independent manner. Those transcripts encode proteins involved in endoplasmic reticulum stress, apoptosis, and amino acid starvation.
2006-08-23 | E-MEXP-817 | biostudies-arrayexpress
Project description:VCP is an evolutionary conserved ubiquitin-dependent ATPase that mediates the degradation of proteins through the ubiquitin-proteasome pathway. Despite the central role of VCP in the regulation of protein homeostasis, identity and nature of its cellular substrates remain poorly defined. Here, we combined chemical inhibition of VCP and quantitative ubiquitin remnant profiling to assess the effect of VCP inhibition on the ubiquitin-modified proteome and to probe the substrate spectrum of VCP in human cells. We demonstrate that inhibition of VCP perturbs cellular ubiquitylation and increases ubiquitylation of a different subset of proteins compared to proteasome inhibition. VCP inhibition globally upregulates K6-linked ubiquitylation that is dependent on the HECT-type ubiquitin E3 ligase HUWE1. We report ~450 putative VCP substrates, many of which function in nuclear processes, including gene expression, DNA repair and cell cycle. Moreover, we identify that VCP regulates the level and activity of the transcription factor c-Myc.
2018-02-08 | GSE107313 | GEO
Project description:The expression of the soluble protein GPNMB (glycoprotein non-metastatic melanoma protein B) induces an aggressive behavior of tumor cells by promoting proliferation and distant spread. The main molecular feature is the over expression of interleukin Il-33. The gene profile of MCA-1-GPNMB and MCA-1-GPNMB-spheroid cell line was assessed against MCA-1-Mock.
2020-07-30 | E-MTAB-8082 | biostudies-arrayexpress