Dataset Information

Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.

ABSTRACT: Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited evidence of lipid dysmetabolism, autophagy dysregulation and deficient phagocytosis, a canonical microglia function. Mutant PFN1 also displayed enhanced binding affinity for PI3P, a critical signaling molecule involved in autophagic and endocytic processing. Our cumulative data implicate a gain-of-toxic function for mutant PFN1 within the autophagic and endo-lysosomal pathways, as administration of rapamycin rescued phagocytic dysfunction in ALS-PFN1 iMGs. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and implicate microglial vesicular degradation pathways in the pathogenesis of these disorders.

SUBMITTER: Funes S

PROVIDER: S-EPMC10954694 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.

Funes Salome S Jung Jonathan J Gadd Del Hayden DH Mosqueda Michelle M Zhong Jianjun J Shankaracharya Unger Matthew M Stallworth Karly K Cameron Debra D Rotunno Melissa S MS Dawes Pepper P Fowler-Magaw Megan M Keagle Pamela J PJ McDonough Justin A JA Boopathy Sivakumar S Sena-Esteves Miguel M Nickerson Jeffrey A JA Lutz Cathleen C Skarnes William C WC Lim Elaine T ET Schafer Dorothy P DP Massi Francesca F Landers John E JE Bosco Daryl A DA

Nature communications 20240320 1

Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibite ...[more]

PMID: 38509062

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Project description:Human induced pluripotent stem cells (iPSCs), together with 21st century cell culture methods, have the potential to better model human physiology with applications in toxicology, disease modeling, and the study of host-pathogen interactions. Several models of the human brain have been developed recently, demonstrating cell-cell interactions of multiple cell types with physiologically relevant 3D structures. Most current models, however, lack the ability to represent the inflammatory response in the brain because they do not include a microglial cell population. Microglia, the resident immunocompetent phagocytes in the central nervous system (CNS), are not only important in the inflammatory response and pathogenesis; they also function in normal brain development, strengthen neuronal connections through synaptic pruning, and are involved in oligodendrocyte and neuronal survival. Here, we have successfully introduced a population of human microglia into 3D human iPSC-derived brain spheres (BrainSpheres, BS) through co-culturing cells of the Immortalized Human Microglia - SV40 cell line with the BS model (μBS). We detected an inflammatory response to lipopolysaccharides (LPS) and flavivirus infection, which was only elicited in the model when microglial cells were present. A concentration of 20 ng/mL of LPS increased gene expression of the inflammatory cytokines interleukin-6 (IL-6), IL-10, and IL-1β, with maximum expression at 6-12 h post-exposure. Increased expression of the IL-6, IL-1β, tumor necrosis factor alpha (TNF-α), and chemokine (C-C motif) ligand 2 (CCL2) genes was observed in μBS following infection with Zika and Dengue Virus, suggesting a stronger inflammatory response in the model when microglia were present than when only astrocyte, oligodendrocyte, and neuronal populations were represented. Microglia innately develop within cerebral organoids (Nature communications), our findings suggest that the μBS model is more physiologically relevant and has potential applications in infectious disease and host-pathogen interactions research.

Dataset Information

Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.

Publications

Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.

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