Group C Niemann‐Pick disease: faulty regulation of low‐density lipoprotein uptake and cholesterol storage in cultured fibroblasts

Pentchev, Peter G.; Comly, Marcella E.; Kruth, Howard S.; Tokoro, T.; Butler, J D; Sokol, Jacob; Filling-Katz, M. R.; Quirk, Jane M.; Marshall, Daniela; Patel, Seema

doi:10.1096/fasebj.1.1.3609608

Cited by 182 publications

(93 citation statements)

References 14 publications

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“…In both shNPC1 and shNPC2 cells, total cellular cholesterol was increased by approximately 2-fold compared with control cells. To examine the effects of NPC1/2 on the intracellular distribution pattern of cholesterol, we employed the fl uorescent fungal macrolide fi lipin, which selectively binds to free (unesterifi ed) cholesterol in membranes ( 57 ), and is a primary tool for diagnosing NPC disease ( 2,58 ). In control IHH cells, fi lipin fl uorescence outlined free cholesterol exclusively in the cells' plasma membranes ( Fig.…”

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confidence: 99%

Altered vitamin E status in Niemann-Pick type C disease

Ulatowski

Parker

Davidson

et al. 2011

Journal of Lipid Research

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Section: Downloaded Frommentioning

confidence: 99%

Altered vitamin E status in Niemann-Pick type C disease

Ulatowski

Parker

Davidson

et al. 2011

Journal of Lipid Research

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“…Niemann-Pick type C disease (NPC) is a rare autosomal recessive lysosomal storage disorder with accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes (Pentchev et al 1987;Zervas et al 2001a, b). The incidence is about 1/150,000 live births (Vanier and Millat 2003).…”

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confidence: 99%

Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C

et al. 2011

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Introduction: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that leads to progressive neurodegeneration. The glucosylceramide synthase blocker miglustat is being used to treat NPC, but monitoring of disease progression and treatment response is difficult. NPC patients have elevated cerebrospinal fluid (CSF) levels of total-tau (T-tau) indicating axonal degeneration, and increased CSF amyloid b (Ab) indicating abnormal brain amyloid metabolism, but it is unknown if start of miglustat treatment affects these biomarker levels.Methods: Biomarkers were measured in serial CSF samples from NPC patients who started miglustat between samplings (N ¼ 5), were untreated at both samplings (N ¼ 5) or received treatment during the whole study (N ¼ 6) (median time between samplings 309 days [range 175-644]). CSF was analyzed for Ab 38 , Ab 40 , Ab 42 , a-cleaved soluble APP, b-cleaved soluble APP, T-tau and phospho-tau.Results: T-tau levels decreased in patients who started miglustat treatment (median 955 [range 338-1,271] ng/L at baseline vs. 382 ng/L at follow-up, p ¼ 0.043). Untreated patients and continuously treated patients had stable levels (p > 0.05). No changes were seen in the other biomarkers.Conclusion: Reduced CSF T-tau suggests that miglustat treatment might affect axonal degeneration in NPC. However, the results must be interpreted with caution and verified in future studies, since this pilot study was small, treatment was not randomized, and patients starting treatment had higher baseline CSF T-tau than untreated patients.

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“…Substantial cell death, particularly in the cerebellum, accounts for some of the symptoms. At the cellular level, mutant cells accumulate cholesterol and other lipids in aberrant compartments with features of late endosomes and lysosomes, and the normal homeostatic response to this excess cholesterol is abolished (2)(3)(4).…”

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The integrity of a cholesterol-binding pocket in Niemann–Pick C2 protein is necessary to control lysosome cholesterol levels

Binkley

Sidow

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The neurodegenerative disease Niemann-Pick Type C2 (NPC2) results from mutations in the NPC2 (HE1) gene that cause abnormally high cholesterol accumulation in cells. We find that purified NPC2, a secreted soluble protein, binds cholesterol specifically with a much higher affinity (K d ‫؍‬ 30 -50 nM) than previously reported. Genetic and biochemical studies identified single amino acid changes that prevent both cholesterol binding and the restoration of normal cholesterol levels in mutant cells. The amino acids that affect cholesterol binding surround a hydrophobic pocket in the NPC2 protein structure, identifying a candidate sterol-binding location. On the basis of evolutionary analysis and mutagenesis, three other regions of the NPC2 protein emerged as important, including one required for efficient secretion.point mutants ͉ secretion ͉ protein evolution N iemann-Pick Type C (NPC) is an autosomal-recessive disorder characterized by progressive ataxia, dystonia, and dementia (1). Substantial cell death, particularly in the cerebellum, accounts for some of the symptoms. At the cellular level, mutant cells accumulate cholesterol and other lipids in aberrant compartments with features of late endosomes and lysosomes, and the normal homeostatic response to this excess cholesterol is abolished (2-4).Our understanding of the molecular basis of this disease has progressed substantially over the last several years, because the two genes damaged by NPC mutations, NPC1 and NPC2, have been identified (5-7). NPC1 encodes a multiple-membranespanning protein containing sequences similar to the sterol cleavage activating protein (SCAP) regulator of cholesterol metabolism and the receptor Patched, a transducer of the Hedgehog family of protein signals. Mutations in NPC1 are responsible for Ϸ95% of the NPC cases (8). The exact role that NPC1 plays in maintaining normal levels of cholesterol in late endosomes and lysosomes remains mysterious. Even less is known about the NPC2 [human epididymis (HE1)] protein, the loss of which is responsible for 5% of NPC cases.NPC2 is a small secreted glycoprotein originally identified as a transcript enriched in the HE1 (9). The porcine HE1 homolog was reported to bind cholesterol with micromolar affinity (K d ϭ 2.3 M; ref. 10), information that was crucial in identifying HE1 as a candidate npc2 gene product (7). However, the similarity between the reported K d and the solubility of cholesterol in aqueous solution (5 M, Merck Index) warrants reexamination of the strength and specificity of this interaction. If the binding is meaningful, NPC2 activity could be altered when cholesterol is bound, thus serving as a sensor of cholesterol levels, accessibility, or location. Alternatively, NPC2 could process or transport cholesterol. Resolving these questions is crucial for determining why cholesterol accumulates in people lacking functional NPC2 protein and for designing rational treatment strategies.In this report, we combine in vitro binding experiments, genetic analysis, a quantitative cell-based ...

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Group C Niemann‐Pick disease: faulty regulation of low‐density lipoprotein uptake and cholesterol storage in cultured fibroblasts

Cited by 182 publications

References 14 publications

Altered vitamin E status in Niemann-Pick type C disease

Altered vitamin E status in Niemann-Pick type C disease

Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C

The integrity of a cholesterol-binding pocket in Niemann–Pick C2 protein is necessary to control lysosome cholesterol levels

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