Gene/Protein Disease Symptom Drug Enzyme Compound
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Previous studies employing rabbit polyclonal anti-human liver ferritin have shown an absence of L ferritin immunoreactivity in liver and spleen tissue from patients with Niemann-Pick disease type C1 (NPC1). The great majority of NPC cases is caused by defects of the NPC1 gene, and a minority by those of another (NPC2). In this study using polyclonal and monoclonal antibodies we show the deficiency of H and L ferritin isoforms in various NPC tissues, including fetal NPC1, not previously described. In particular, evidence is provided for deficiency in H and L ferritins in tissues, except lung, from a patient with Niemann-Pick disease type C2 (NPC2). The present findings indicate that H and L ferritins are deficient in both NPC types characterized by accumulation of unesterified cholesterol and additional metabolites in the endosomal/lysosomal system. We hypothesize that the lesions in NPC1 and NPC2 block the intracellular utilization not only of cholesterol, but also that of iron for the synthesis of cytosolic ferritin.
Mol Genet Metab 2000 Jul
PMID:Deficient ferritin immunoreactivity in tissues from niemann-pick type C patients: extension of findings to fetal tissues, H and L ferritin isoforms, but also one case of the rare Niemann-Pick C2 complementation group. 1092 74

Niemann-Pick C (NPC) disease is a recessive cholesterol storage disorder characterized by severe, progressive neurodegeneration. The primary causative gene found on chromosome 18q11-12 was identified by a positional cloning approach. The NPC1 gene product is predicted to be a large polytopic glycoprotein with a cytoplasmic tail containing a dileucine endosome-targeting motif. The NPC1 protein sequence shares strong homology with a newly identified homologue, NPC1L1, and the morphogen receptor Patched. In addition, a group of five NPC1 transmembrane domains share homology with the sterol-sensing domain of proteins involved in cellular cholesterol homeostasis. Subcellular localization studies have shown NPC1 to reside in late endosomes and to transiently associate with lysosomes and the trans-Golgi network. Analysis of its topological arrangement in membranes suggests that NPC1 contains 13 transmembrane domains and three large, hydrophilic, lumenal loops. Currently, there is no direct evidence as to the function of the NPC1 protein; however, a number of observations suggest that NPC1 may be related to a family of prokaryotic efflux pumps and thus it may also act as a molecular pump.
Mol Genet Metab
PMID:The structure and function of the Niemann-Pick C1 protein. 1100 8

Holoprosencephaly, or an undivided forebrain, is a complex brain malformation associated with Sonic hedgehog (Shh) mutations. Other causes of holoprosencephaly have converged upon the Shh signaling pathway: genetic and pharmacologic impairment of cholesterol synthesis, and the action of the steroidal alkaloid cyclopamine. This review focuses on recent studies aimed at determining how Shh signaling is affected by these causes of holoprosencephaly, whether they involve a common mechanism and the role played by cholesterol. Cholesterol is potentially important for both biogenesis of Shh and in signal transduction in Shh-responsive cells. Teratogens that induce holoprosencephaly appear to affect Shh signal transduction rather than Shh biogenesis. Analysis of these agents and other compounds that affect various aspects of cellular cholesterol distribution indicates that the role of cholesterol in Shh signal transduction is novel and complicated. The similarity of the Shh receptor, Patched (Ptc), to the Niemann-Pick Cl protein, which is involved in the vesicular trafficking of cholesterol, provides insight into the role of cholesterol and the action of compounds like cyclopamine.
Cell Mol Life Sci 2000 Nov
PMID:The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly. 1113 Jan 77

People homozygous for mutations in the Niemann-Pick type C1 (NPC1) gene have physiological defects, including excess accumulation of intracellular cholesterol and other lipids, that lead to drastic neural and liver degeneration. The NPC1 multipass transmembrane protein is resident in late endosomes and lysosomes, but its functions are unknown. We find that organelles containing functional NPC1-fluorescent protein fusions undergo dramatic movements, some in association with extending strands of endoplasmic reticulum. In NPC1 mutant cells the NPC1-bearing organelles that normally move at high speed between perinuclear regions and the periphery of the cell are largely absent. Pulse-chase experiments with dialkylindocarbocyanine low-density lipoprotein showed that NPC1 organelles function late in the endocytic pathway; NPC1 protein may aid the partitioning of endocytic and lysosomal compartments. The close connection between NPC1 and the drug U18666A, which causes NPC1-like organelle defects, was established by rescuing drug-treated cells with overproduced NPC1. U18666A inhibits outward movements of NPC1 organelles, trapping membranes and cholesterol in perinuclear organelles similar to those in NPC1 mutant cells, even when cells are grown in lipoprotein-depleted serum. We conclude that NPC1 protein promotes the creation and/or movement of particular late endosomes, which rapidly transport materials to and from the cell periphery.
Mol Biol Cell 2001 Mar
PMID:Dynamic movements of organelles containing Niemann-Pick C1 protein: NPC1 involvement in late endocytic events. 1125 Oct 74

Studies of Niemann-Pick C (NPC) and Tangier diseases have led to the identification of the causative genes, NPC1 and ABCA1, respectively. Characterization of their protein products shows that NPC1 and ABCA1 are permeases that belong to two different superfamilies of efflux pumps, which might be important in subcellular lipid and cholesterol transport.
Nat Rev Mol Cell Biol 2001 Sep
PMID:Multidrug permeases and subcellular cholesterol transport. 1153 23

Niemann-Pick type C disease is a progressive neurological disease with cholesterol storage in liver, and npc1-/- mice share these features and are sterile. We have searched for the cause of sterility and found normal folliculogenesis and progesterone levels but lack of implantation. Multiple drug resistance (MDR) P-glycoproteins are plasma membrane proteins implicated in the movement of drugs and lipids across membranes. Their functions are inhibited by progesterone, which has been shown to alter cellular cholesterol homeostasis and has implicated P-glycoproteins in the movement of cholesterol to the endoplasmic reticulum. We have introduced the mdr1a knockout into the npc1 mutant line. While the neurological disease continues at its usual rate, preventing the females from taking care of their litters, npc1-/-, mdr1a-/- females became fertile. Although the mdr1a P-glycoprotein co-localizes with caveolae, neither caveolin-1 nor npc1 levels were significantly altered in the livers of double homozygotes. The absence of mdr1a was confirmed by immunoblotting, but npc1 deficiency was not associated with consistent changes in cerebellar mdr1a in mdr1a+/+ mice. The results show that a mdr1a mutation is an in vivo suppressor of female sterility in npc1 deficient mice.
Mol Reprod Dev 2002 Jun
PMID:mdr1a deficiency corrects sterility in Niemann-Pick C1 protein deficient female mice. 1198 26

The nuclear oxysterol receptors liver X receptor-alpha [LXRalpha (NR1H3)] and LXRbeta (NR1H2) coordinately regulate genes involved in cholesterol homeostasis. Although both LXR subtypes are expressed in the brain, their roles in this tissue remain largely unexplored. In this report, we show that LXR agonists have marked effects on gene expression in murine brain tissue both in vitro and in vivo. In primary astrocyte cultures, LXR agonists regulated several established LXR target genes, including ATP binding cassette transporter A1, and enhanced cholesterol efflux. In contrast, little or no effect on gene expression or cholesterol efflux was detected in primary neuronal cultures. Treatment of mice with a selective LXR agonist resulted in the induction of several LXR target genes related to cholesterol homeostasis in the cerebellum and hippocampus. These data provide the first evidence that the LXRs regulate cholesterol homeostasis in the central nervous system. Because dysregulation of cholesterol balance is implicated in central nervous system diseases such as Alzheimer's and Niemann-Pick disease, pharmacological manipulation of the LXRs may prove beneficial in the treatment of these disorders.
Mol Endocrinol 2002 Jun
PMID:Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system. 1204 22

The RSH/Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/mental retardation syndrome caused by an inborn error of cholesterol synthesis. Mutations in the 3beta-hydroxysteroid Delta(7)-reductase gene result in impaired enzymatic reduction of 7-dehydrocholesterol (7-DHC) to cholesterol. Cells obtain cholesterol by either de novo synthesis or from exogenous sources by the binding and uptake of low density lipoprotein (LDL) particles. Because de novo synthesis of cholesterol is impaired in SLOS, current investigational therapy for SLOS consists of dietary cholesterol supplementation. However, the potential effects of elevated intracellular levels of 7-DHC on intracellular LDL metabolism have not been described. We now report that in addition to the primary defect in de novo cholesterol synthesis, SLOS fibroblasts have a secondary defect of LDL cholesterol metabolism. Staining of fibroblasts with filipin, a fluorescent polyene antibiotic which binds unesterified sterols, shows that SLOS fibroblasts accumulate unesterified sterols. Further studies show that this increased filipin staining was due to an abnormal accumulation of LDL derived cholesterol rather than due to storage of endogenously synthesized 7-dehydrocholesterol (7-DHC). We have also found that SLOS fibroblasts failed to degrade LDL at a normal rate, and examination of SLOS fibroblasts by electron microscopy demonstrated the formation of lysosomal inclusions similar to that seen in Niemann-Pick type C (NPC) cells. We propose that 7-DHC may directly or indirectly inhibit the function of the NPC protein through its sterol-sensing domain (SSD), and that 7-DHC may perturb the function of other SSD containing proteins in SLOS.
Mol Genet Metab 2002 Apr
PMID:Cholesterol storage defect in RSH/Smith-Lemli-Opitz syndrome fibroblasts. 1205 64

To maintain proper cellular function, the amount and distribution of cholesterol residing within cellular membranes must be regulated. The principal disorder affecting transport of cholesterol through the late endosomal/lysosomal system and intracellular cholesterol homeostasis is Niemann-Pick type C (NPC) disease. The genes responsible for NPC disease have been identified, and the encoded Niemann-Pick C1 (NPC1) and Niemann-Pick C2 (HE1/NPC2) proteins are currently the subject of intense investigation. This review provides a detailed examination of NPC1 and HE1/NPC2 in regulating the transport of cholesterol through the late endosomal/lysosomal system to other cellular compartments responsible for maintaining intracellular cholesterol homeostasis, and how defective function of these proteins may be responsible for the pathophysiology associated with NPC disease.
Curr Mol Med 2002 Aug
PMID:The Niemann-Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system. 1212 14

Niemann-Pick type C (NPC) disease is a rare inherited metabolic disorder characterized by hepatosplenomegaly, progressive neurodegeneration, and storage of lipids such as cholesterol and glycosphingolipids in most tissues. The current study was conducted to characterize the Niemann-Pick C1 (NPC1) protein in feline fibroblasts. This was accomplished by generating rabbit polyclonal antibodies against a peptide corresponding to amino acids 1256-1275 of the feline NPC1 protein. The results obtained using immunoblot analysis identified two major proteins that migrated at approximately 140 and 180 kDa. These two proteins were absent when immunoblots were incubated in the presence of feline NPC1 antibody and immunizing peptide, or preimmune serum. Fluorescence microscopy of feline fibroblasts incubated with the feline NPC1 antibody revealed granular staining within the perinuclear region of the cell. This granular staining was diminished when feline fibroblasts were incubated in the presence of feline NPC1 antibody and immunizing peptide, or was completely absent when feline fibroblasts were incubated in the presence of preimmune serum. Additional studies using double-labeled fluorescence microscopy indicated that feline NPC1 partially colocalized with markers for late endosomes/lysosomes, endoplasmic reticulum, and microtubules, but not the trans-Golgi network. In summary, the results presented in this report demonstrate that the NPC1 protein in feline fibroblasts has a similar distribution as that previously described for human and murine fibroblasts.
Mol Genet Metab 2002 May
PMID:The Niemann-Pick C1 protein in feline fibroblasts. 1217 78


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