NPC1 lipidomics by LC-MS and FAMEs by GC-MS
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Agilent 7820A GC-MS, Agilent 6546 QTOF
ORGANISM(S): Homo Sapiens Mus Musculus
SUBMITTER: 
Stephanie Cologna
PROVIDER: MSV000084098 | MassIVE | Tue Jul 16 17:32:00 BST 2019
REPOSITORIES: MassIVE
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Project description:Lipidomics in the liver of late-stage NPC1 with a focus on fatty acid metabolism.
2019-07-16 | MSV000084098 | GNPS
Project description:Lipidomic analysis of murine liver tissue reveals altered fatty acids in NPC1. Shotgun lipidomics of whole liver tissue. GC-MS analysis of FAME including omega-3 and omega-6 standards.
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Project description:Lipidomic analysis of murine liver tissue reveals altered fatty acids in NPC1. Shotgun lipidomics of whole liver tissue. GC-MS analysis of FAME including omega-3 and omega-6 standards.
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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:Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional neurological, lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1-/- mice (Npc1nih)relative to Npc1+/- at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates for the neurological disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including GaucherM-bM-^@M-^Ys disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1-/- as well as Balb/c Npc1nmf164 mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1-/- mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. We used microarrays on the diseased organs, brain, liver and spleen of the Npc1-/- mice to unserstand the molecular changes occur during the progression of NPC diseases. From the data, we have identified 12 potential genes which can be potentially developed as blood-based biomarker. We have also discovered up regulation of innate iimunity genes in all three organs of Npc1-/- mice and functionally validated them in liver and spleen. Brain from 11 female Npc1M-bM-^HM-^R/M-bM-^HM-^R and 16 control female mice (Npc1+/+ and Npc1+/M-bM-^HM-^R) from 6 age groups (20-25, 37-40, 54-55, 59-62, 67-71 and 81-84 days) were surgically harvested. Liver and spleen from 6 Npc1-/- and 6 Npc1+/- female mice from three age group ( 20-25, 54-55 and 67-71 days) were surgically harvested. Organs were kept in RNA later and stored at -20 M-BM-0C until used. RNA was isolated and Affymetrix mouse 430 2.0 array hybridizations were performed by M-bM-^@M-^XUCLA Clinical Microarray CoreM-bM-^@M-^Y, UCLA, Los Angeles, CA, USA. Subsequent raw data were analyzed using DNA-Chip Analyzer (D-Chip) with the .CEL files obtained from AGCC. Data from Npc1-/- mice from all age groups were compared to control mice (Npc1+/- and/or Npc1-/- mice) from all age groups separately for brain, liver and spleen. 'Matrix Table1' corrsponds for brain, 'Matrix Table2' corresponds for liver and 'Matrix Table3' corresponds for spleen. Thresholds for selecting significant genes were set at a relative difference M-BM-31.5-fold, absolute difference M-BM-3100 signal intensity units and p<0.05. Genes that met all three criteria simultaneously were considered as significant change.
2012-12-27 | E-GEOD-39621 | biostudies-arrayexpress
Project description:Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional neurological, lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1-/- mice (Npc1nih)relative to Npc1+/- at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates for the neurological disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher’s disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1-/- as well as Balb/c Npc1nmf164 mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1-/- mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. We used microarrays on the diseased organs, brain, liver and spleen of the Npc1-/- mice to unserstand the molecular changes occur during the progression of NPC diseases. From the data, we have identified 12 potential genes which can be potentially developed as blood-based biomarker. We have also discovered up regulation of innate iimunity genes in all three organs of Npc1-/- mice and functionally validated them in liver and spleen.
2012-12-27 | GSE39621 | GEO
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 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 (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: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.
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