Identification of a pharmaceutical compound that partially corrects the Niemann-Pick C phenotype in cultured cells

Liscum, Laura; Arnio, Emily; Anthony, Monique; Howley, Andrea; Sturley, Stephen L.; Agler, Michele

doi:10.1194/jlr.m200179-jlr200

Cited by 15 publications

(9 citation statements)

References 44 publications

(33 reference statements)

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“…These studies have largely had limited effect on the NPC disease phenotype. The compounds that have been examined include statin drugs (lovastatin and pravastatin) [28][29][30], a squalene synthesis inhibitor (CP-340868) [31], cholestyramine [28,29], nicotinic acid [28], ezetimibe (Zetia) [32], peroxisomal inducers (clofibrate, perfluorooctanoic acid, dehydroepiandrosterone, and diethylhexylphthalate) [33,34], neurosteroids or their mimics (allopregnanolone, ganaxolone, and T-0901317) [35,36], oxysterols (25-and 27-hydroxycholesterol, 7-ketocholesterol, and 17b-estradiol) [17,[37][38][39][40], synthetic liver X receptor ligands (T-0901317 and bexarotene) [40][41][42][43], sphingolipid pathwaytargeting agents (miglustat and n -butyldeoxygalactonojirimycin) [44][45][46], calcium regulators (curcumin, thapsigargin, and myriocin; note that curcumin is also an HDACi) [47][48][49], apoptosis inhibitors (imatinib, minocycline, and B-cell lymphoma 2 protein) [50,51], a neurodegeneration inhibitor (N ω -nitro-L-arginine methyl ester) [52], α-tocopherol (vitamin E) [53,54], tamoxifen [53], nitrovin (difurazone) [55], and several members of 3 heterocycle series consisting of highly substituted pyrrolinones, triazines, and thiadiazoles [56][57][58][59]. Low cholesterol diets have been found to be ineffective …”

Section: Therapies Tested Previously For Treatment Of Npc Diseasementioning

confidence: 99%

Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

Helquist

Maxfield

Wiech³

et al. 2013

Neurotherapeutics

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Section: Therapies Tested Previously For Treatment Of Npc Diseasementioning

confidence: 99%

Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

Helquist

Maxfield

Wiech³

et al. 2013

Neurotherapeutics

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“…Cholesterol Depletion-For cholesterol depletion, H4 cells were grown for 24 h in Opti-MEM with 10% fetal bovine serum and then for 24 h in either DMEM supplemented with 2 mM L-glutamine, 10% delipidated fetal bovine serum (Cocalico Biologicals), 20 M lovastatin (Calbiochem), and 0.5 mM mevalonate (mevalonolactone, Sigma) or DMEM with 10% complete fetal bovine serum (34). Prior to experimentation, cells were incubated for 10 min in DMEM with 10 mM methyl ␤-cyclodextrin (M␤-CD, Sigma) or DMEM alone.…”

Section: Generation Of Expression Constructs Of Lrp and Bace And Bacementioning

confidence: 99%

The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel β-Secretase (BACE1) Substrate

Arnim

Kinoshita

Peltan

et al. 2005

Journal of Biological Chemistry

232

176

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BACE is a transmembrane protease with ␤-secretase activity that cleaves the amyloid precursor protein (APP). After BACE cleavage, APP becomes a substrate for ␥-secretase, leading to release of amyloid-␤ peptide (A␤), which accumulates in senile plaques in Alzheimer disease. APP and BACE are co-internalized from the cell surface to early endosomes. APP is also known to interact at the cell surface and be internalized by the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic and signaling receptor. Using a new fluorescence resonance energy transfer (FRET)-based assay of protein proximity, fluorescence lifetime imaging (FLIM), and co-immunoprecipitation we demonstrate that the light chain of LRP interacts with BACE on the cell surface in association with lipid rafts. Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane. Taken together, these data suggest that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a novel BACE substrate. BACE1 (␤ site of APP-cleaving enzyme) is a type I membrane-associated aspartyl protease that cleaves APP (1-4). Besides APP, the few BACE substrates that have been identified include the APP homologues APLP1 and -2 (5), P-selectin glycoprotein ligand-1 (PSGL-1), and a membrane-bound sialyltransferase (6). Post-translational processing of BACE involves N-glycosylation, removal of its prodomain by a furin-like protease, and further complex glycosylation (7-9). After glycosylation, BACE co-traffics with APP and is rapidly transported to the Golgi apparatus and distal secretory pathway (9). Measurable amounts of APP and BACE are present on the plasma membrane (10 -12) and in lipid rafts (12)(13)(14). BACE and APP are internalized from the cell surface to early endosomes and cycle between the cell membrane and endosomes (10,11,15).The low density lipoprotein receptor-related protein, LRP, is a type I integral membrane protein with a 515-kDa extracellular ␣-chain non-convalently bound to the 85 kDa membranespanning ␤-chain. It is also found on the cell surface and cycles between the cell membrane and endosomes. Multiple intracellular adaptor and scaffolding proteins bind the LRP 100 amino acid cytoplasmic tail (16, 17); its four extracellular binding domains mediate endocytosis of a wide array of ligands, including several of potential importance for Alzheimer disease pathophysiology: APP, apolipoprotein E and ␣ 2 -macroglobulin (16 -18). The LRP ligand binding domains interact with KPIcontaining forms of APP. In addition, an interaction between the C-terminal domain of APP and LRP, mediated by the cytoplasmic adaptor protein Fe65, impacts APP internalization (18 -23). In addition to its role in endocytosis, LRP has an interesting pattern of proteolysis that parallels APP in some ways. Ectodomain shedding of LRP has been described (24) and proteolysis of LRP by matrix metalloproteas...

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“…Although the time course can be variable, symptoms often develop in early childhood, and the disease is usually fatal by the teens. There have been attempts to develop treatments for NPC (3)(4)(5)(6)(7)(8), but no effective therapy exists at present.…”

mentioning

confidence: 99%

Automated microscopy screening for compounds that partially revert cholesterol accumulation in Niemann-Pick C cells

Pipalia¹,

Huang²,

Ralph

et al. 2006

Journal of Lipid Research

132

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Niemann-Pick disease type C (NPC) is an autosomal recessive genetic disorder manifested by abnormal accumulation of unesterified cholesterol and other lipids. We screened combinatorially synthesized chemical libraries to identify compounds that would partially revert cholesterol accumulation. Cultured CHO cells with NPC phenotypes (CT60 and CT43) were used for screening along with normal CHO cells as a control. We developed an automated microscopy assay based on imaging of filipin fluorescence for estimating cholesterol accumulation in lysosomal storage organelles. Our primary screen of 14,956 compounds identified 14 hit compounds that caused significant reduction in cellular cholesterol accumulation at 10 MM. We then screened a secondary library of 3,962 compounds selected based on chemical similarity to the initial hits and identified 7 compounds that demonstrated greater efficacy and lower toxicity than the original hits. These compounds are effective at concentrations of 123 nM to 3 MM in reducing the cholesterol accumulation in cells with a NPC1 phenotype.-Pipalia, N.

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Identification of a pharmaceutical compound that partially corrects the Niemann-Pick C phenotype in cultured cells

Cited by 15 publications

References 44 publications

Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel β-Secretase (BACE1) Substrate

Automated microscopy screening for compounds that partially revert cholesterol accumulation in Niemann-Pick C cells

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