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Niemann-Pick type C1 unfractionated cerebellum and cerebral cortex proteomics

ABSTRACT: label-free quantification using 11 week mouse tissue lysates from non fractionated cerebellum and cerebral cortex of wild type and NPC1 null mice.

INSTRUMENT(S): Agilent 6550 QTOF

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Stephanie Cologna

PROVIDER: MSV000082042 | MassIVE | Thu Feb 08 13:36:00 GMT 2018

REPOSITORIES: MassIVE

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11 week Niemann-Pick type C1 Mouse Cerebellum and Cerebral Cortex Proteomics

Project description:Label-free quantification of cerebellum and cerebral cortex proteomics in 11 week wild type and NPC1 null mice

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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.

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Project description:Niemann-Pick disease type C (NPC) is a rare fatal neurodegenerative lysosomal storage disease caused by mutations of either NPC1 or NPC2. NPC2 is a soluble lysosomal protein that in coordination with NPC1 is responsible for the efflux of unesterified cholesterol from the lysosome. Mutations of both genes cause a similar cellular pathology, that includes the accumulation of unesterified cholesterol and other lipids in the late endosome/lysosome, while reducing cholesterol bioavailability. Here we describe a npc2 null zebrafish model generated by CRISPR/Cas9 gene targeting. Zygotic npc2m/m zebrafish from the intercross of npc2+/m individuals showed significant unesterified cholesterol accumulation at larval stages, and a reduction in body size in adulthood. Additionally, zygotic npc2m/m adults exhibited motor and balance defects shortly before a premature death. These findings mimic defects found in human and mice, however the phenotype at embryonic stages were milder than expected. To address the possible dose protection effects of npc2 mRNA present in the oocyte at the time of fertilization we intercrossed npc2m/m zebrafish to generate Maternal-zygotic (MZ) npc2m/m embryos. MZnpc2m/m zebrafish exhibited significant developmental defects including absent otolith, abnormal head/brain development, curved/twisted body axis, no circulating blood cells, and died by 72 hpf. These developmental defects have not previously been reported in connection with either NPC2 or NPC1. RNA-seq analysis conducted on 30 hpf npc2+/m and MZnpc2m/m embryos revealed a significant reduction in notch3 expression as well as reduction in other downstream genes in the signally pathway such as hey1 and her12 that could be partially rescued by microinjection of a plasmid containing the constitutively active notch3 ICD at the 1-cell stage, suggesting that impaired Notch3 signaling likely underlies some aspects of the developmental defects observed in MZnpc2m/m zebrafish.

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