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

A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.

Project description: Not available

| S-EPMC11465669 | biostudies-literature

Derlin-1 regulates mutant VCP-linked pathogenesis and endoplasmic reticulum stress-induced apoptosis.

Project description: Not available

| S-EPMC4177747 | biostudies-literature

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