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Neuron-specific changes in gene expression caused by NPC1 deficiency

ABSTRACT: Background: Niemann-Pick type C is a rare autosomal recessive lysosomal storage disorder presenting aggravating neurologic symptoms due degeneration of specific types of CNS neurons. At present, it is not well understood how neurons react to NPC1 deficiency and why some neuronal cell types are more vulnerable than others. Purpose: We took aimed to uncover how a specific type of CNS neuron that can be highly purified reacts to NPC1 deficiency based on changes in gene expression. Methods: Retinal ganglion cells were purified from individual one-week old Balb/c mice homozygous for a mutant NPC1 allele (NPC1m1N) and wildtype littermates (n = 4 mice each genotype) using immunopanning. Total RNA was isolated from acutely isolated neurons and subjected to RNAseq using 4 biological replicates for each genotype. Results: Our analysis revealed a strong downregulation of transcripts known to be decreased in mutant mice including Npc1 and Calb1 thus validating our approach. We observed a strong upregulation of genes for cellular cholesterol accretion and the downregulation of those for cholesterol release. Other changes including downregulation genes involved in the immune response and synaptic components. Conclusions: The observed changes suggest that neurons already at one week of age sense a cholesterol deficit because lipids accumulate in the endosomal-lysosomal system and cannot be redistributed intracellularly. Gene expression analysis by RNAseq in retinal ganglion cells acutely purified from eight-days-old NPC1-deficient mice and wildtype littermates

ORGANISM(S): Mus musculus

SUBMITTER: Frank Pfrieger

PROVIDER: E-GEOD-75775 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Neuron-specific changes in gene expression caused by NPC1 deficiency

Project description:Background: Niemann-Pick type C is a rare autosomal recessive lysosomal storage disorder presenting aggravating neurologic symptoms due degeneration of specific types of CNS neurons. At present, it is not well understood how neurons react to NPC1 deficiency and why some neuronal cell types are more vulnerable than others. Purpose: We took aimed to uncover how a specific type of CNS neuron that can be highly purified reacts to NPC1 deficiency based on changes in gene expression. Methods: Retinal ganglion cells were purified from individual one-week old Balb/c mice homozygous for a mutant NPC1 allele (NPC1m1N) and wildtype littermates (n = 4 mice each genotype) using immunopanning. Total RNA was isolated from acutely isolated neurons and subjected to RNAseq using 4 biological replicates for each genotype. Results: Our analysis revealed a strong downregulation of transcripts known to be decreased in mutant mice including Npc1 and Calb1 thus validating our approach. We observed a strong upregulation of genes for cellular cholesterol accretion and the downregulation of those for cholesterol release. Other changes including downregulation genes involved in the immune response and synaptic components. Conclusions: The observed changes suggest that neurons already at one week of age sense a cholesterol deficit because lipids accumulate in the endosomal-lysosomal system and cannot be redistributed intracellularly.

2016-07-27 | GSE75775 | GEO

The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells snRNA-Seq

Project description:Cholesterol is required for oligodendrocyte maturation and CNS myelination. Here, we demonstrate an essential role for the intracellular cholesterol transporter NPC1 in these processes. NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann-Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. To identify cell types and pathways affected early in pathogenesis, we performed single nuclear RNA-seq on the forebrain of Npc1-/- mice at P16. This analysis uncovered striking transcriptional changes in the oligodendrocyte lineage during the period of developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. Unexpectedly, we identified a significant upregulation of genes associated with neurogenesis and synapse formation in Npc1-/- oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3 and H3K9me3.

2023-05-31 | GSE221609 | GEO

The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells ChIP-seq

2023-05-31 | GSE219007 | GEO

The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells bulk RNA-seq of mouse OPCs

2023-05-31 | GSE221336 | GEO

Global gene expression change in the cerebellum of Niemann-Pick disease type C mice with deletion of Ccl3 or Purkinje neuron-specific NPC1 rescue

Project description:Macrophage inflammatory protein 1alpha/CCL3 protein is a known pro-inflammatory cytokine that can mediate chemotaxis of monocytes and promote cell degranulation. Ccl3 gene expression is elevated in the CNS and visceral tissue of many lysosomal storage disorders. The deletion of Ccl3 in a mouse model of Sandhoff disease was reported to result in reduced monocyte-associated pathology in the brain, delayed neurodegeneration, and prolonged health. However, deletion of Ccl3 in a mouse model of Niemann-Pick C disease was dentrimental or neutral instead of beneficial. Prevention of neuronal loss was instead mediated by providing NPC1 to neurons. We used microarrays to detail the global change in gene expression of the cerebellum in Niemann-Pick C disease animals, Niemann-Pick C disease animals with Ccl3 gene deletion, and Niemann-Pick C disease animals with Purkinje neuron-specific NPC1-YFP rescue. To identify the top ~50 genes elevated in NPC disease Npc1-/- (NPC) and Npc1+/- (WT) mice were compared at age P50; To profile changes in gene expression as a result of Ccl3 gene deletion Ccl3-/-;Npc1-/- mice were compared against Npc1-/- mice across various ages; To profile changes in gene expression as a result of Purkinje neuron-sepcific NPC1 rescue P;N;Npc1-/- mice were compared against Npc1-/- mice across various ages.

2012-04-16 | E-GEOD-36119 | biostudies-arrayexpress

Presenilin deficiency results in cellular cholesterol accumulation by impairment of protein glycosylation and NPC1 function.

Project description:Presenilin (PS) proteins represent the catalytic subunits of γ-secretase, and play a critical role in the generation of the Amyloid β (Aβ) peptide and the pathogenesis of Alzheimer’s disease (AD). Indeed, mutations in presenilin 1 (PS1) or PS2 are a major cause of early onset familial Alzheimer’s disease (FAD). However, PS proteins also exert multiple functions beyond Aβ generation. In this study, we examine the individual roles of PS1 and PS2 in cellular cholesterol metabolism. Deletion of PS1 or PS2 in mouse models led to cholesterol accumulation in cerebral neurons. Cholesterol accumulation was also observed in lysosomes of embryonic fibroblasts from PS1-KO and PS2-KO mice, and associated with decreased expression of the Niemann-Pick type C1 (NPC1) protein involved in intracellular cholesterol transport at late endosome/lysosome. Mass spectrometry and complementary biochemical methods also revealed abnormal N-glycosylation of NPC1 and several other membrane proteins in PS1-KO and PS2-KO cells. Interestingly, pharmacological inhibition of N-glycosylation resulted in intracellular cholesterol accumulation prominently in lysosomes as well as decrease of NPC1 expression in wild-type MEFs, thereby resembling the changes in PS1-KO and PS2-KO MEFs. In turn, treatment of PS1-KO and PS2-KO MEFs with a chaperone inducer, Arimoclomol, attenuated decrease of NPC1 and rescued the lysosomal cholesterol accumulation. Additionally, the intracellular cholesterol accumulation in PS1-KO and PS2-KO MEFs was prevented by NPC1 overexpression. Collectively, these data indicate that PS/γ-secretase dysfunction results in an impairment of protein N-glycosylation, which eventually causes NPC1 decrease and intracellular cholesterol accumulation. 3'RNASeq of mouse embryonic fibroblasts with PS1- or PS2-deficiency compared with controls. Biological replicates

2024-05-26 | GSE223572 | GEO

NPC1 regulates the distribution of phosphatidylinositol 4 kinases at Golgi and Lysosome membranes

Project description:Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KIIα and PI4KIIIβ-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease.

2021-09-15 | MTBLS2612 | MetaboLights

Proteomic analysis of bone-marrow derived macrophages from NPC1 KO mice

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. To study the effect of NPC1 deficiency on the innate immune system, we performed proteomics on bone-marrow derived macrophages (BMDMs) of NPC1 KO and WT mice. Without further treatment or activation, BMDMs of NPC1 KO mice showed alterations mainly related to cholesterol metabolism, which is in line with the intracellular cholesterol transport function of NPC1.

2024-12-05 | PXD056249 | Pride

A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export

Project description:Cholesterol import in mammalian cells is mediated by the LDL receptor pathway. Here, we perform a genome-wide CRISPR screen using an endogenous cholesterol reporter and identify >100 genes involved in LDL-cholesterol import. We characterise C18orf8 as a core subunit of the mammalian Mon1-Ccz1 guanidine exchange factor (GEF) for Rab7, required for complex stability and function. C18orf8-deficient cells lack Rab7 activation and show severe defects in late endosome morphology and endosomal LDL trafficking, resulting in cellular cholesterol deficiency. Unexpectedly, free cholesterol accumulates within swollen lysosomes, suggesting a critical defect in lysosomal cholesterol export. We find that active Rab7 interacts with the NPC1 cholesterol transporter and licenses lysosomal cholesterol export. This process is abolished in C18orf8-, Ccz1- and Mon1A/B-deficient cells and restored by a constitutively active Rab7. The trimeric Mon1-Ccz1-C18orf8 (MCC) GEF therefore plays a central role in cellular cholesterol homeostasis coordinating Rab7 activation, endosomal LDL trafficking and NPC1-dependent lysosomal cholesterol export.

2020-10-29 | PXD021444 | Pride

Transcription profiling of mouse developing retinal ganglion and amacrine cells reveals molecular heterogeneity of

Project description:During development of the central nervous system (CNS), cycling uncommitted progenitor cells give rise to a variety of distinct neuronal and glial cell types. As these different cell types are born, they progress from newly specified cells to fully differentiated neurons and glia. In order to define the developmental processes of individual cell types, single cell expression profiling was carried out on developing ganglion and amacrine cells of the murine retina. Individual cells from multiple developmental stages were isolated and profiled on Affymetrix oligonucleotide arrays. These experiments have yielded an expanded view of the processes underway in developing retinal ganglion and amacrine cells, as well as several hundred new marker genes for these cell types. In addition, this study has allowed for the definition of some of the molecular heterogeneity both between developing ganglion and amacrine cells and among subclasses of each cell type. Experiment Overall Design: Single retinal cells were isolated in tubes containing lysis buffer, their mRNAs were reverse transcribed, and the resulting cDNAs were PCR amplified for 35 cycles. Labeled cDNA samples were hybridized to Affymetrix 430 2.0 microarrays and the data was normalized using MAS5.0 software. Cells were identified post hoc as either developing retinal ganglion cells, amacrine cells or rod photoreceptor cells.

2008-06-16 | E-GEOD-9812 | biostudies-arrayexpress

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