RNA-seq of isogenic NPC1 mutant iPSC-derived microglia like cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE184243 | GEO | 2021/09/18
REPOSITORIES: GEO
Similar Datasets
Project description:Niemann-Pick type C (NPC) disease is a rare neurodegenerative disorder mainly caused by autosomal recessive mutations in Npc1 which result in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is one of the prominent pathological features, consequences of NPC1 loss on microglial function and disease outcome remain largely unknown. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in an NPC1-deficient (Npc1-/-) murine model. We demonstrate that microglial defects, including enhanced phagocytosis and impaired lipid trafficking, occur early in the NPC pathological cascade and precede neuronal death. Compromised microglial function during Npc1-/- mouse development is reflected by enhanced synaptic pruning and deficient turnover of myelin. Accumulation of the undigested myelin occurs mainly within multi-vesicular bodies (MVBs) of Npc1-/- microglia and not within lysosomes. This is in agreement with the impairments in recycling of myelin into lipid droplets. Macrophages of NPC patients displayed similar molecular and functional alterations as murine Npc1-/- microglia, strengthening the role of NPC1 in immune homeostasis. Generated ex vivo assays using patient macrophages are novel promising clinical tools to monitor the progression and therapeutic efficacy in NPC patients.
2021-02-09 | PXD019447 | Pride
Project description:Niemann-Pick type C (NPC) disease is a rare neurodegenerative disorder mainly caused by autosomal recessive mutations in Npc1 which result in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is one of the prominent pathological features, consequences of NPC1 loss on microglial function and disease outcome remain largely unknown. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in an NPC1-deficient (Npc1-/-) murine model. We demonstrate that microglial defects, including enhanced phagocytosis and impaired lipid trafficking, occur early in the NPC pathological cascade and precede neuronal death. Compromised microglial function during Npc1-/- mouse development is reflected by enhanced synaptic pruning and deficient turnover of myelin. Accumulation of the undigested myelin occurs mainly within multi-vesicular bodies (MVBs) of Npc1-/- microglia and not within lysosomes. This is in agreement with the impairments in recycling of myelin into lipid droplets. Macrophages of NPC patients displayed similar molecular and functional alterations as murine Npc1-/- microglia, strengthening the role of NPC1 in immune homeostasis. Generated ex vivo assays using patient macrophages are novel promising clinical tools to monitor the progression and therapeutic efficacy in NPC patients.
2021-02-09 | PXD019452 | Pride
Project description:RNA-seq of isogenic NPC1 mutant iPSC-derived microglia like cells
| PRJNA763793 | ENA
Project description:Purkinje cells (PC) of the cerebellum degenerate in adult mice with mutations in the Niemann-Pick type C (NPC) disease 1 (Npc1) gene. We subjected BALB/c Npc1+/+ and Npc1-/- mouse cerebella from an early and a later time point of PC degeneration to a genome-wide microarray gene expression analysis. We found general underrepresentation of PC-specific transcripts, consistent with PC loss, and elevated markers of microglia activation at the later time point. Experiment Overall Design: 12 BALB/c Npc1 mice of the two ages P21 and P49 and the two genotypes Npc1+/+ and Npc1-/- were used, 3 replicates for each age and genotype. The animals were of the same breed and lived under identical housing conditions. All except one animal were female. The animals were not further treated, but only sacrificed at P21 or P49.
2008-06-14 | E-GEOD-5944 | biostudies-arrayexpress
Project description:Purkinje cells (PC) of the cerebellum degenerate in adult mice with mutations in the Niemann-Pick type C (NPC) disease 1 (Npc1) gene. We subjected BALB/c Npc1+/+ and Npc1-/- mouse cerebella from an early and a later time point of PC degeneration to a genome-wide microarray gene expression analysis. We found general underrepresentation of PC-specific transcripts, consistent with PC loss, and elevated markers of microglia activation at the later time point. Keywords: Niemann-Pick type C, Purkinje cell degeneration
2007-07-01 | GSE5944 | GEO
Project description:Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in NPC1 gene, causing lipid accumulation within late endosomes/lysosomes, and resulting in progressive neurodegeneration. Although microglial activation proceeds neuronal loss, it remains elusive whether loss of NPC1 in microglia actively contributes to NPC pathology. Here, we used a mouse model with depletion of NPC1 in myeloid cells to investigate the role of microglia in Niemann-Pick disease. In order to achieve the loss of NPC1 in myeloid cells, mice with floxed Npc1 alleles (Npc1 flox/flox) were crossed with mice expressing the constitutively active Cre recombinase under the myeloid-specific promotor of Cx3cr1. Hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including shortened lifespan, motor impairments, astrogliosis, neuroaxonal pathology and increased levels of neuronal injury biomarker NF-L. To study the differential vulnerability between the brain regions, we compared the cerebellar with the cerebral (brain without cerebellum) proteome in Cre- and Cre+ mice at late pathological stages. Our results suggest that microglial loss of NPC1 has profound effects on brain cell homeostasis especially in the cerebrum.
2024-12-05 | PXD056188 | Pride
Project description:Niemann-Pick Type C disease is an autosomal recessive neurodegenerative disorder with abnormal lipid storage as the major cellular pathologic hallmark. Genetic analyses have identified mutations in NPC1 gene in the great majority of cases, while mutations in NPC2 account for the remainders. Yet, little is known regarding the cellular mechanisms responsible for NPC pathogenesis, especially for neurodegeneration, which is the usual cause of death. To identify critical steps that could account for the pathological manifestations of the disease in one of the most affected brain structures, we performed global gene expression analysis in the cerebellum from three-week old Npc1+/+ and Npc1-/- mice with two different microarray platforms (Agilent and Illumina). Our results provide novel molecular insight regarding the mechanisms of pathogenesis in NPC disease and reveal potential new therapeutic targets. We performed global gene expression analysis in the cerebellum from three-week old Npc1+/+ and Npc1-/- mice with two different microarray platforms (Agilent and Illumina). Differentially-expressed genes identified by both microarray platforms were then subjected to KEGG pathway analysis. Expression of genes in six pathways was significantly altered in Npc1-/- mice; functionally, these signaling pathways belong to the following three categories: 1) steroid and terpenoid biosynthesis, 2) immune response, and 3) cell adhesion/motility. In addition, the expression of several proteins involved in lipid transport was significantly altered in Npc1-/- mice.
2010-08-30 | E-GEOD-20450 | biostudies-arrayexpress
Project description:Niemann-Pick Type C disease is an autosomal recessive neurodegenerative disorder with abnormal lipid storage as the major cellular pathologic hallmark. Genetic analyses have identified mutations in NPC1 gene in the great majority of cases, while mutations in NPC2 account for the remainders. Yet, little is known regarding the cellular mechanisms responsible for NPC pathogenesis, especially for neurodegeneration, which is the usual cause of death. To identify critical steps that could account for the pathological manifestations of the disease in one of the most affected brain structures, we performed global gene expression analysis in the cerebellum from three-week old Npc1+/+ and Npc1-/- mice with two different microarray platforms (Agilent and Illumina). Our results provide novel molecular insight regarding the mechanisms of pathogenesis in NPC disease and reveal potential new therapeutic targets.
2010-08-31 | GSE20450 | GEO
Project description:To compare the proteome between PFN1 mutant and PFN1 WT iPSC-microglia under baseline conditions
2024-02-18 | PXD038943 | Pride
Project description:Microglia are specialised brain-resident macrophages that arise from primitive macrophages colonising the embryonic brain. Microglia contribute to multiple aspects of brain development, but their precise roles in early human brain remain poorly understood due to limited access to relevant tissues. The generation of brain organoids from induced human pluripotent stem cells (iPSC) recapitulates some key features of human embryonic brain development, but current approaches do not incorporate microglia and thus are lacking. Here, we generated microgliasufficient brain organoids by co-culturing brain organoids with primitive-like macrophages generated from the same human iPSC (iMac). In organoid co-cultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro), and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2+ lipid droplets that exported cholesterol and its esters which weretaken up by NPC in the organoids. We also detected PLIN2+ lipid droplet-loaded microglia in mouse and human embryonic brain. Overall, our approach significantly advances current human brain organoid approaches by incorporating microglial
2023-11-15 | GSE241127 | GEO