Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB DOI Creative Commons
Benjamin Clarke, Oliver J. Ziff, Giulia E. Tyzack

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Nov. 26, 2024

Abstract Background Microglia play crucial roles in maintaining neuronal homeostasis but have been implicated contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia ALS/FTD remains incompletely understood. Methods Here, we generated highly enriched cultures VCP mutant derived from human induced pluripotent stem cells (hiPSCs) investigate their cell autonomous non-cell ALS pathogenesis. We used RNA-sequencing, proteomics functional assays study hiPSC effects on motor neurons astrocytes. Results Transcriptomic, proteomic analyses revealed immune lysosomal dysfunction microglia. Stimulating healthy with inflammatory inducer lipopolysaccharide (LPS) showed partial overlap reactive transformation. LPS-stimulated displayed differential activation pathways compared Conserved gene expression changes were identified between microglia, SOD1 mice postmortem spinal cord microglial signatures, including increased transmembrane glycoprotein GPNMB . While knockdown affected phagocytosis processes this was not sufficient ameliorate phenotypes Secreted factors activate JAK-STAT pathway Conclusions undergo transformation involving that partially recapitulate key other models post mortem tissue. These occur independently Additionally, elicit non responses astrocytes pathway.

Language: Английский

Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB DOI Creative Commons
Benjamin Clarke, Oliver J. Ziff, Giulia E. Tyzack

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Nov. 26, 2024

Abstract Background Microglia play crucial roles in maintaining neuronal homeostasis but have been implicated contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia ALS/FTD remains incompletely understood. Methods Here, we generated highly enriched cultures VCP mutant derived from human induced pluripotent stem cells (hiPSCs) investigate their cell autonomous non-cell ALS pathogenesis. We used RNA-sequencing, proteomics functional assays study hiPSC effects on motor neurons astrocytes. Results Transcriptomic, proteomic analyses revealed immune lysosomal dysfunction microglia. Stimulating healthy with inflammatory inducer lipopolysaccharide (LPS) showed partial overlap reactive transformation. LPS-stimulated displayed differential activation pathways compared Conserved gene expression changes were identified between microglia, SOD1 mice postmortem spinal cord microglial signatures, including increased transmembrane glycoprotein GPNMB . While knockdown affected phagocytosis processes this was not sufficient ameliorate phenotypes Secreted factors activate JAK-STAT pathway Conclusions undergo transformation involving that partially recapitulate key other models post mortem tissue. These occur independently Additionally, elicit non responses astrocytes pathway.

Language: Английский

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