Disease relevance of Npc1

• By 7 weeks of age, the sterol pool in the NPC mice had increased from 2,165 to 5,669 mg/kg body weight because of the daily sequestration of 67 mg of cholesterol per kg in the various organs [1].
• Niemann-Pick type C (NPC) is a neurodegenerative disorder with somatically altered cholesterol metabolism [2].
• Both human and murine NPC are characterized neuropathologically by ballooned neurons distended with lipid storage, axonal spheroid formation, demyelination, and widespread neuronal loss [3].
• The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1(-/-) mice, and the beneficial effects were found to be greater than with the single injection at day 7 [4].
• We found significant but relatively small improvements in rate of disease progression by treating Npc1-/- mice with tamoxifen and/or vitamin E. Some sex differences in response and an early improvement in Rota-Rod performance suggest areas for further study [5].

Psychiatry related information on Npc1

• The events underlying NPC progressive neurodegeneration are poorly understood but include neurofibrillary tangles of the type found in Alzheimer's disease [6].

High impact information on Npc1

• Disordered cholesterol trafficking might disrupt neurosteroidogenesis, thereby contributing to the NP-C phenotype [7].
• Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive, childhood neurodegenerative disease [7].
• Decreased production of allopregnanolone apparently contributes to the pathology of NP-C; thus, neurosteroid treatment may be useful in ameliorating progression of the disease [7].
• Neonatal administration of allopregnanolone delays the onset of neurological symptoms, increases Purkinje and granule cell survival, reduces cortical GM2 and GM3 ganglioside accumulation and doubles the lifespan of NP-C mice [7].
• Here we show that NP-C mouse brain contains substantially less neurosteroid than wild-type brain and has an age-related decrease in the ability to synthesize 5alpha-dihydroprogesterone and allopregnanolone [7].

Chemical compound and disease context of Npc1

• We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1(-/-) mice) [4].
• We investigated the effects of tamoxifen and vitamin E (D-alpha tocopherol) treatment on patterns of weight loss and motor function in the mouse model of Niemann-Pick C disease (Npc1-/- mice) [5].
• To understand the functions of neurosteroids during nervous system development, we used two mouse models: one, in which the cyp17 gene was ablated, thus ablating synthesis of the neurosteroid DHEA, and a second, in a mouse model of a human childhood fatal neurodegenerative disease, Niemann-Pick Type C (NP-C) [8].
• Recently, the authors have established immortalized Schwann cell lines derived from Niemann-Pick disease type C mice (NPC; spm/spm) and globoid cell leukodystrophy mice (twitcher) [9].

Biological context of Npc1

• Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene [10].
• Nuclear concentrations and DNA binding activity of NF-kappaB's transactivation subunit, p65, were significantly reduced in Npc1-/- mice compared to Npc1+/+ mice [6].
• In adult animals of both genotypes, the Npc1 mRNA was detected in the majority of neurons in nearly all regions, but at significantly higher levels in the cerebellum and in specific pontine nuclei [11].
• Niemann-Pick type C (NPC) disease is caused by mutations to genes that encode proteins critical to intracellular lipid homeostasis [6].
• To define further the relationship between caveolin-1 function and the cholesterol trafficking defect in NPC, we examined the expression and distribution of additional caveolar and signal transduction proteins [12].

Anatomical context of Npc1

• Synaptic vesicles from Npc1(-/-) mice have normal cholesterol content but altered protein composition [13].
• To identify the location of Npc1 inside the cerebellum, we performed immunostaining with an anti-Npc1 antibody in primary rat cerebellar cultures identifying reactive Purkinje neurons by double-labeling with the Purkinje specific marker calbindin and sub-populations of glial cells [14].
• At birth, when there is little myelin in the CNS, the concentration of cholesterol is significantly elevated in every region of the brain in the homozygous NPC mouse [15].
• In the NPC mouse brain, cholesterol accumulates in late endosomes/lysosomes [16].
• In contrast, the triacylglycerol content of Npc1(-/-) hepatocytes was 50% lower than of Npc1(+/+) hepatocytes [17].

Associations of Npc1 with chemical compounds

• Furthermore, net loss of cholesterol from the CNS is much higher in the NPC mouse than in the control animal (2.23 versus 1.37 mg/day per kg) so that the concentration of sterol in most regions of the brain is reduced [15].
• We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1(-/-) mice, presumably by effects on myelination or neuronal connectivity [4].
• Furthermore, the steroid treatment also increased myelination in brains of Npc1(-/-) mice [4].
• GSL and cholesterol levels were increased in mutant NPC1-null Chinese hamster ovary cells as well as U18666A and progesterone induced NPC cell culture models [18].
• Altered BODIPY lactosylceramide targeting, decreased endocytic uptake of a fluid phase marker, and mistargeting of annexin 2 (phenotypes associated with NPC) are reversed by inhibition of GSL synthesis [18].
• We focused on the role of the AP-3 pathway in the targeting of the mammalian NP-C proteins [19].
• These results provide strong evidence that cholesterol accumulation-induced changes in autophagy-lysosome function are closely associated with neurodegeneration in NPC [20].

Physical interactions of Npc1

• Niemann-Pick type C (NPC) disease is a disorder of intracellular transport where glycosphingolipids (GSLs) and cholesterol accumulate in endosomal compartments [18].

Regulatory relationships of Npc1

• Serum cholesterol was increased in the controls but not the Npc1-/- mice on the high-fat diet; it was massively increased in the Ldlr-/- mice [21].

Other interactions of Npc1

• Perturbations of nuclear factor (NF)-kappaB, which is regulated by GSK-3beta, occurred in Npc1-/- mouse brains [6].
• Here, we analyze the effects of genetically depriving NPC neurons of complex gangliosides by creating mice doubly deficient in both NPC1 and the GSL synthetic enzyme, GM2/GD2 synthase (GalNAcT) [22].
• Using the BALB/c murine model for NPC disease, we found that the expression of caveolin-1 in total liver homogenates from heterozygous and homozygous affected animals was altered [23].
• Our data suggest that focal deregulation of cdk5/p25 in axons leads to cytoskeletal abnormalities and eventual neurodegeneration in NPC [3].
• Serum alanine aminotransferase was elevated in Npc1-/- mice on the regular diet and frequently became markedly elevated with the high-fat diet [21].

Analytical, diagnostic and therapeutic context of Npc1

• We have used in situ hybridization techniques to characterize the pattern of Npc1 mRNA expression in both the wild-type and the npc(nih) mutant mouse brain [11].
• In conclusion, Npc1-/- mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis [21].
• Based on a highly homologous domain, we designed primers to look for levels of Npc1 mRNA with a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) approach using cyclophilin as an internal standard [14].
• The decreased sperm number in Npc1(-/-) mice is due, at least in part, to partial arrest of spermatogenesis in the testes, as revealed by histological analysis [24].
• The sciatic nerve of the mouse mutant with Niemann-Pick type C disease (NPC mouse) was investigated using light and electron microscopy, and teased-fiber preparations [25].

References