Journal articles: 'NPCL'

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Cong, Shuang, Yaying Sun, Jinrong Lin, Shaohua Liu, and Jiwu Chen. "A Synthetic Graft With Multilayered Co-Electrospinning Nanoscaffolds for Bridging Massive Rotator Cuff Tear in a Rat Model." American Journal of Sports Medicine 48, no. 8 (May 26, 2020): 1826–36. http://dx.doi.org/10.1177/0363546520917684.

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Background: Graft bridging is used in massive rotator cuff tear (MRCT); however, the integration of graft-tendon and graft-bone is still a challenge. Hypothesis: A co-electrospinning nanoscaffold of polycaprolactone (PCL) with an “enthesis-mimicking” (EM) structure could bridge MRCT, facilitate tendon regeneration, and improve graft-bone healing. Study Design: Controlled laboratory study. Methods: First, we analyzed the cytocompatibility of the electrospinning nanoscaffolds, including aligned PCL (aPCL), nonaligned PCL (nPCL), aPCL–collagen I, nPCL–collagen II, and nPCL-nanohydroxyapatite (nHA). Second, for the EM condition, nPCL–collagen II and nPCL-nHA were electrospun layer by layer at one end of the aPCL–collagen I; for the control condition, the nPCL was electrospun on the aPCL. In 40 mature male rats, resection of both the supraspinatus and infraspinatus tendons was performed to create MRCT, and the animals were divided randomly into EM and control groups. In both groups, one end of the layered structure was fixed on the footprint of the rotator cuff, whereas the other end of the layered structure was sutured with the tendon stump. The animals were euthanized for harvesting of tissues for histologic and biomechanical analysis at 4 weeks or 8 weeks postoperatively. Results: All scaffolds showed good cytocompatibility in vitro. The graft-tendon tissue in the EM group had more regularly arranged cells, denser tissue, a significantly higher tendon maturing score, and more birefringence compared with the control group at 8 weeks after operation. Newly formed fibrocartilage could be observed at the graft-bone interface in both groups by 8 weeks, but the EM group had a higher graft-bone healing score and significantly more newly formed fibrocartilage than the control group. An enthesis-like structure with transitional layers was observed in the EM group at 8 weeks. Biomechanically, the values for maximum failure load and stiffness of the tendon-graft-bone complex were significantly higher in the EM group than in the control group at 8 weeks. Conclusion: The co-electrospinning nanoscaffold of aPCL–collagen I could be used as a bridging graft to improve early graft-tendon healing for MRCT in a rat model and enhance early enthesis reconstruction in combination with a multilayered structure of nPCL–collagen II and nPCL-nHA. Clinical Relevance: We constructed a graft to bridge MRCT, enhance graft-tendon healing and graft-bone healing, and reconstruct the enthesis structure.

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Song, Jun, Mei Liu, Zhanping Yang, Songwei Xu, Bowen Cheng, and Pengfei Fei. "Synthesis and characterization of cellulose acetate naphthoate with good ultraviolet and chemical resistance." e-Polymers 17, no. 4 (June 27, 2017): 333–40. http://dx.doi.org/10.1515/epoly-2016-0293.

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AbstractCommercial cellulose diacetate with a degree of substitution (DS) of 2.45 was partly deacetylated to cellulose acetate (CA) with different DSs by acid-catalyzed hydrolysis and then reacted with 1-naphthoyl chloride (NpCl) to synthesize CA naphthoate (CANp). Fourier transform infrared and 1H-NMR were used to characterize the chemical structure of CANp. The DS of naphthoate moiety (DSCANp) could be varied from 0.18 to 0.98 by adjusting the molar ratio of –OH in CA unit to NpCl, the DS of CA (DSCA), and the reaction time and temperature. When DSCA was 2.01 and the molar ratio was 1:6, the maximum DSCANp of the product was achieved after a reaction at 80°C for 2 h. With the increase of DSCANp, the thermal stability decreased slightly whereas the anti-ultraviolet property was enhanced. Moreover, the obtained films containing CANp exhibited good ultraviolet resistance as well as chemical resistance.

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Kitagawa, Wataru, Nobutada Kimura, and Yoichi Kamagata. "A Novel p-Nitrophenol Degradation Gene Cluster from a Gram-Positive Bacterium, Rhodococcus opacus SAO101." Journal of Bacteriology 186, no. 15 (August 1, 2004): 4894–902. http://dx.doi.org/10.1128/jb.186.15.4894-4902.2004.

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ABSTRACT p-Nitrophenol (4-NP) is recognized as an environmental contaminant; it is used primarily for manufacturing medicines and pesticides. To date, several 4-NP-degrading bacteria have been isolated; however, the genetic information remains very limited. In this study, a novel 4-NP degradation gene cluster from a gram-positive bacterium, Rhodococcus opacus SAO101, was identified and characterized. The deduced amino acid sequences of npcB, npcA, and npcC showed identity with phenol 2-hydroxylase component B (reductase, PheA2) of Geobacillus thermoglucosidasius A7 (32%), with 2,4,6-trichlorophenol monooxygenase (TcpA) of Ralstonia eutropha JMP134 (44%), and with hydroxyquinol 1,2-dioxygenase (ORF2) of Arthrobacter sp. strain BA-5-17 (76%), respectively. The npcB, npcA, and npcC genes were cloned into pET-17b to construct the respective expression vectors pETnpcB, pETnpcA, and pETnpcC. Conversion of 4-NP was observed when a mixture of crude cell extracts of Escherichia coli containing pETnpcB and pETnpcA was used in the experiment. The mixture converted 4-NP to hydroxyquinol and also converted 4-nitrocatechol (4-NCA) to hydroxyquinol. Furthermore, the crude cell extract of E. coli containing pETnpcC converted hydroxyquinol to maleylacetate. These results suggested that npcB and npcA encode the two-component 4-NP/4-NCA monooxygenase and that npcC encodes hydroxyquinol 1,2-dioxygenase. The npcA and npcC mutant strains, SDA1 and SDC1, completely lost the ability to grow on 4-NP as the sole carbon source. These results clearly indicated that the cloned npc genes play an essential role in 4-NP mineralization in R. opacus SAO101.

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Fujiwara, Akimasa, and Junyi Zhang. "Development of a Scheduling Model for Car Tourists’ 1-Day Tours." Transportation Research Record: Journal of the Transportation Research Board 1921, no. 1 (January 2005): 100–111. http://dx.doi.org/10.1177/0361198105192100112.

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Focusing on car tourists’ 1-day tours, a new scheduling model combines a nested paired combinatorial logit (NPCL) type of destination and route choice model and a time allocation (TA) model. The NPCL model, developed previously from the generalized extreme value family of discrete choice models to represent the similarity between pairs of alternatives in the same choice nest as well as the influence of inclusive value, indicates destination choice in the bottom level and route choice in the top level. The TA model applies Becker's theory to determine the time allocated to each touring site. Utility of destination choice is influenced by the time spent at each site. Different route choices result in a level of service for the road network that varies hourly, varying available time used in the TA model. The TA model endogenously incorporates the influence of hourly variance in level of service at the site of interest, which is affected by the allocated time. An iteration estimation procedure is proposed to estimate the parameters consistently in both models. Finally, revealed preference tourist travel survey data collected in a tourist attraction region near the Sea of Japan indicate that the proposed scheduling model is effective in representing car tourists’ scheduling behavior for 1-day tours.

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Chen, Yixin, Yu Sang, Jianchun Guo, Jian Yang, Weihua Chen, Fei Liu, Ji Zeng, and Botao Tang. "Synthesis and Characterization of a Novel Self-Generated Proppant Fracturing Fluid System." Energies 15, no. 22 (November 21, 2022): 8737. http://dx.doi.org/10.3390/en15228737.

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Hydraulic fracturing is an important technology for the stimulation of oil and gas reservoirs. Conventional fracturing technology based on “sand-carrying” faces some challenges such as sand plugs; incompatibility with the well completion method; damage to the reservoir caused by the incomplete gel-breaking of the fracturing fluid; solid proppants inefficiently turning the corner in complex fracture networks, and so on. In this paper, a novel self-generated proppant fracturing fluid system is proposed to solve the above problems caused by “sand-carrying”. The advantage of the fracturing fluid system is that in the whole process of fracturing, no solid proppants will be injected. The fracturing fluid itself will transform into solid proppants in the induced fractures under high temperatures to resist fracture closure stress. The fluid system consists of two kinds of liquids. One is the phase change liquid (PCL), which occurs as a liquid–solid phase change at high-formation temperatures to form a solid proppant. The other is the non-phase change liquid (NPCL), which controls the dispersity of the PCL in the two-phase fluid system. The main building block of the PCL is confirmed to be the bisphenol-A diglycidyl ether-type epoxy resin, whereas the NPCL is mainly composed of surfactants. The viscosity, phase-change temperature, and time of the fracturing fluid system are, respectively, about 30 mPa·s, 80 °C, and 20 min.

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Dardis, Andrea, Eleonora Pavan, Martina Fabris, Rosalia Maria Da Riol, Annalisa Sechi, Agata Fiumara, Lucia Santoro, et al. "Plasma Neurofilament Light (NfL) in Patients Affected by Niemann–Pick Type C Disease (NPCD)." Journal of Clinical Medicine 10, no. 20 (October 19, 2021): 4796. http://dx.doi.org/10.3390/jcm10204796.

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(1) Background: Niemann–Pick type C disease (NPCD) is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. The clinical presentation is characterized by visceral and neurological involvement. Apart from a small group of patients presenting a severe perinatal form, all patients develop progressive and fatal neurological disease with an extremely variable age of onset. Different biomarkers have been identified; however, they poorly correlate with neurological disease. In this study we assessed the possible role of plasma NfL as a neurological disease-associated biomarker in NPCD. (2) Methods: Plasma NfL levels were measured in 75 healthy controls and 26 patients affected by NPCD (24 NPC1 and 2 NPC2; 39 samples). (3) Results: Plasma NfL levels in healthy controls correlated with age and were significantly lower in pediatric patients as compared to adult subjects (p = 0.0017). In both pediatric and adult NPCD patients, the plasma levels of NfL were significantly higher than in age-matched controls (p < 0.0001). Most importantly, plasma NfL levels in NPCD patients with neurological involvement were significantly higher than the levels found in patients free of neurological signs at the time of sampling, both in the pediatric and the adult group (p = 0.0076; p = 0.0032, respectively). Furthermore, in adults the NfL levels in non-neurological patients were comparable with those found in age-matched controls. No correlations between plasma NfL levels and NPCD patient age at sampling or plasma levels of cholestan 3β-5α-6β-triol were found. (4) Conclusions: These data suggest a promising role of plasma NfL as a possible neurological disease-associated biomarker in NPCD.

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Pogány, Peter, and Attila Kovács. "Theoretical investigation of NpC, NpC2 and NpC4 molecules." Structural Chemistry 26, no. 5-6 (August 4, 2015): 1309–22. http://dx.doi.org/10.1007/s11224-015-0641-5.

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Li, Xiaochun, Piyali Saha, Jian Li, Günter Blobel, and Suzanne R. Pfeffer. "Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2." Proceedings of the National Academy of Sciences 113, no. 36 (August 22, 2016): 10079–84. http://dx.doi.org/10.1073/pnas.1611956113.

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Export of LDL-derived cholesterol from lysosomes requires the cooperation of the integral membrane protein Niemann–Pick C1 (NPC1) and a soluble protein, Niemann–Pick C2 (NPC2). Mutations in the genes encoding these proteins lead to Niemann–Pick disease type C (NPC). NPC2 binds to NPC1’s second (middle), lumenally oriented domain (MLD) and transfers cholesterol to NPC1’s N-terminal domain (NTD). Here, we report the 2.4-Å resolution crystal structure of a complex of human NPC1–MLD and NPC2 bearing bound cholesterol-3-O-sulfate. NPC1–MLD uses two protruding loops to bind NPC2, analogous to its interaction with the primed Ebola virus glycoprotein. Docking of the NPC1–NPC2 complex onto the full-length NPC1 structure reveals a direct cholesterol transfer tunnel between NPC2 and NTD cholesterol binding pockets, supporting the “hydrophobic hand-off” cholesterol transfer model.

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Seker Yilmaz, Berna, Julien Baruteau, Ahad A. Rahim, and Paul Gissen. "Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease." International Journal of Molecular Sciences 21, no. 14 (July 17, 2020): 5059. http://dx.doi.org/10.3390/ijms21145059.

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Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0–24) and 7.5 (0–24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.

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Infante, Rodney E., Michael L. Wang, Arun Radhakrishnan, Hyock Joo Kwon, Michael S. Brown, and Joseph L. Goldstein. "NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes." Proceedings of the National Academy of Sciences 105, no. 40 (September 4, 2008): 15287–92. http://dx.doi.org/10.1073/pnas.0807328105.

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Egress of lipoprotein-derived cholesterol from lysosomes requires two lysosomal proteins, polytopic membrane-bound Niemann–Pick C1 (NPC1) and soluble Niemann–Pick C2 (NPC2). The reason for this dual requirement is unknown. Previously, we showed that the soluble luminal N-terminal domain (NTD) of NPC1 (amino acids 25–264) binds cholesterol. This NTD is designated NPC1(NTD). We and others showed that soluble NPC2 also binds cholesterol. Here, we establish an in vitro assay to measure transfer of [3H]cholesterol between these two proteins and phosphatidylcholine liposomes. Whereas NPC2 rapidly donates or accepts cholesterol from liposomes, NPC1(NTD) acts much more slowly. Bidirectional transfer of cholesterol between NPC1(NTD) and liposomes is accelerated >100-fold by NPC2. A naturally occurring human mutant of NPC2 (Pro120Ser) fails to bind cholesterol and fails to stimulate cholesterol transfer from NPC1(NTD) to liposomes. NPC2 may be essential to deliver or remove cholesterol from NPC1, an interaction that links both proteins to the cholesterol egress process from lysosomes. These findings may explain how mutations in either protein can produce a similar clinical phenotype.

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Völkner, Christin, Maik Liedtke, Andreas Hermann, and Moritz J. Frech. "Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1." International Journal of Molecular Sciences 22, no. 2 (January 12, 2021): 710. http://dx.doi.org/10.3390/ijms22020710.

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The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the NPC1 or NPC2 gene. Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark. A total of 95% of cases are due to a deficiency of NPC1 and only 5% are caused by NPC2 deficiency. Clinical manifestations include neurological symptoms and systemic symptoms, such as hepatosplenomegaly and pulmonary manifestations, the latter being particularly pronounced in NPC2 patients. NPC1 and NPC2 are rare diseases with the described neurovisceral clinical picture, but studies with human primary patient-derived neurons and hepatocytes are hardly feasible. Obviously, induced pluripotent stem cells (iPSCs) and their derivatives are an excellent alternative for indispensable studies with these affected cell types to study the multisystemic disease NPC1. Here, we present a review focusing on studies that have used iPSCs for disease modeling and drug discovery in NPC1 and draw a comparison to commonly used NPC1 models.

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Hakim, Aliefman, Abdul Wahab Jufri, Jamaluddin , and Devi Ayu Septiani. "Effect of Natural Product Chemistry Laboratory Based on Sasambo Medicinal Plant (NPCL-SMP) on Metacognition Skills." Creative Education 12, no. 08 (2021): 1840–47. http://dx.doi.org/10.4236/ce.2021.128139.

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Dardis, Andrea, Stefania Zampieri, Cinzia Gellera, Rosalba Carrozzo, Silvia Cattarossi, Paolo Peruzzo, Rosalia Dariol, et al. "Molecular Genetics of Niemann–Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants." Journal of Clinical Medicine 9, no. 3 (March 3, 2020): 679. http://dx.doi.org/10.3390/jcm9030679.

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Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in 105 Italian NPC patients belonging to 83 unrelated families (77 NPC1 and 6 NPC2). NPC1 and NPC2 genes were studied following an algorithm recently published. Eighty-four different NPC1 and five NPC2 alleles were identified. Only two NPC1 alleles remained non detected. Sixty-two percent of NPC1 alleles were due to missense variants. The most frequent NPC1 mutation was the p.F284Lfs*26 (5.8% of the alleles). All NPC2 mutations were found in the homozygous state, and all but one was severe. Among newly diagnosed patients, 18 novel NPC1 mutations were identified. The pathogenic nature of 7/9 missense alleles and 3/4 intronic variants was confirmed by filipin staining and NPC1 protein analysis or mRNA expression in patient’s fibroblasts. Taken together, our previous published data and new results provide an overall picture of the molecular characteristics of NPC patients diagnosed so far in Italy.

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Hodošček, Milan, and Nadia Elghobashi-Meinhardt. "Simulations of NPC1(NTD):NPC2 Protein Complex Reveal Cholesterol Transfer Pathways." International Journal of Molecular Sciences 19, no. 9 (September 4, 2018): 2623. http://dx.doi.org/10.3390/ijms19092623.

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The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, are involved in the lysosomal storage disease, NPC disease. The formation of a NPC1–NPC2 protein–protein complex is believed to be necessary for the transfer of cholesterol and lipids out of the late endosomal (LE)/lysosomal (Lys) compartments. Mutations in either NPC1 or NPC2 can lead to an accumulation of cholesterol and lipids in the LE/Lys, the primary phenotype of the NPC disease. We investigated the NPC1(NTD)–NPC2 protein–protein complex computationally using two putative binding interfaces. A combination of molecular modeling and molecular dynamics simulations reveals atomic details that are responsible for interface stability. Cholesterol binding energies associated with each of the binding pockets for the two models are calculated. Analyses of the cholesterol binding in the two models support bidirectional ligand transfer when a particular interface is established. Based on the results, we propose that, depending on the location of the cholesterol ligand, a dynamical interface between the NPC2 and NPC1(NTD) proteins exists. Structural features of a particular interface can lower the energy barrier and stabilize the passage of the cholesterol substrate from NPC2 to NPC1(NTD).

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Chen, Fannie W., Ronald E. Gordon, and Yiannis A. Ioannou. "NPC1 late endosomes contain elevated levels of non-esterified (‘free’) fatty acids and an abnormally glycosylated form of the NPC2 protein." Biochemical Journal 390, no. 2 (August 23, 2005): 549–61. http://dx.doi.org/10.1042/bj20050236.

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NPC (Niemann–Pick type C) disease is a rare lipidosis characterized by the accumulation of LDL (low-density lipoprotein)-derived non-esterified cholesterol in the E/L (endosomal/lysosomal) system. The gene products that are responsible for the two NPC complementation groups are distinct and dissimilar, yet their cellular and disease phenotypes are virtually indistinguishable. To investigate the relationship between NPC1 and NPC2 and their potential role in NPC disease pathogenesis, we have developed a method for the rapid and efficient isolation of late endocytic vesicles from mouse liver by magnetic chromatography. Late endosomes from Wt (wild-type) and NPC1 mice were found to differ not only in their cholesterol and sphingomyelin content, as expected, but also in their non-esterified (‘free’) fatty acid content, with NPC1 vesicles showing an approx. 7-fold increase in non-esterified fatty acid levels compared with Wt vesicles. Furthermore, we show that the NPC2 protein is in an incompletely deglycosylated form in NPC1 late endosomes by a mechanism that is specific to the NPC2 protein and not a global aberration of protein glycosylation/deglycosylation or trafficking, since NPC2 secreted from NPC1 cells is indistinguishable from that secreted from Wt cells. Also, a greater proportion of the normally soluble cellular NPC2 protein partitions with detergent-insoluble late endosomal internal membrane domains in NPC1 vesicles. In addition, we show that, although a small amount of the NPC2 protein associates with these membranes in Wt vesicles, this localization becomes much more pronounced in NPC1 vesicles. These results suggest that the function of the NPC2 protein may be compromised as well in NPC1 endosomes, which might explain the paradoxical phenotypic similarities of the two NPC disease complementation groups.

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Liedtke, Maik, Christin Völkner, Alexandra V. Jürs, Franziska Peter, Michael Rabenstein, Andreas Hermann, and Moritz J. Frech. "Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T." International Journal of Molecular Sciences 22, no. 8 (April 13, 2021): 4009. http://dx.doi.org/10.3390/ijms22084009.

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Niemann-Pick type C2 (NP-C2) disease is a rare hereditary disease caused by mutations in the NPC2 gene. NPC2 is a small, soluble protein consisting of 151 amino acids, primarily expressed in late endosomes and lysosomes (LE/LY). Together with NPC1, a transmembrane protein found in these organelles, NPC2 accomplishes the exclusion of cholesterol; thus, both proteins are essential to maintain cellular cholesterol homeostasis. Consequently, mutations in the NPC2 or NPC1 gene result in pathophysiological accumulation of cholesterol and sphingolipids in LE/LY. The vast majority of Niemann-Pick type C disease patients, 95%, suffer from a mutation of NPC1, and only 5% display a mutation of NPC2. The biochemical phenotype of NP-C1 and NP-C2 appears to be indistinguishable, and both diseases share several commonalities in the clinical manifestation. Studies of the pathological mechanisms underlying NP-C2 are mostly based on NP-C2 animal models and NP-C2 patient-derived fibroblasts. Recently, we established induced pluripotent stem cells (iPSCs), derived from a donor carrying the NPC2 mutations c.58G>T/c.140G>T. Here, we present a profile of pathophysiological in vitro features, shared by NP-C1 and NP-C2, of neural differentiated cells obtained from the patient specific iPSCs. Profiling comprised a determination of the NPC2 protein level, detection of cholesterol accumulation by filipin staining, analysis of oxidative stress, and determination of autophagy. As expected, the NPC2-deficient cells displayed a significantly reduced amount of NPC2 protein, and, accordingly, we observed a significantly increased amount of cholesterol. Most notably, NPC2-deficient cells displayed only a slight increase of reactive oxygen species (ROS), suggesting that they do not suffer from oxidative stress and express catalase at a high level. As a site note, comparable NPC1-deficient cells suffer from a lack of catalase and display an increased level of ROS. In summary, this cell line provides a valuable tool to gain deeper understanding, not only of the pathogenic mechanism of NP-C2, but also of NP-C1.

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Cianciola, Nicholas L., Diane J. Greene, Richard E. Morton, and Cathleen R. Carlin. "Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1." Molecular Biology of the Cell 24, no. 21 (November 2013): 3309–25. http://dx.doi.org/10.1091/mbc.e12-10-0760.

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Niemann–Pick disease type C (NPC) is caused by mutations in NPC1 or NPC2, which coordinate egress of low-density-lipoprotein (LDL)-cholesterol from late endosomes. We previously reported that the adenovirus-encoded protein RIDα rescues the cholesterol storage phenotype in NPC1-mutant fibroblasts. We show here that RIDα reconstitutes deficient endosome-to-endoplasmic reticulum (ER) transport, allowing excess LDL-cholesterol to be esterified by acyl-CoA:cholesterol acyltransferase and stored in lipid droplets (LDs) in NPC1-deficient cells. Furthermore, the RIDα pathway is regulated by the oxysterol-binding protein ORP1L. Studies have classified ORP1L as a sterol sensor involved in LE positioning downstream of GTP-Rab7. Our data, however, suggest that ORP1L may play a role in transport of LDL-cholesterol to a specific ER pool designated for LD formation. In contrast to NPC1, which is dispensable, the RIDα/ORP1L-dependent route requires functional NPC2. Although NPC1/NPC2 constitutes the major pathway, therapies that amplify minor egress routes for LDL-cholesterol could significantly improve clinical management of patients with loss-of-function NPC1 mutations. The molecular identity of putative alternative pathways, however, is poorly characterized. We propose RIDα as a model system for understanding physiological egress routes that use ORP1L to activate ER feedback responses involved in LD formation.

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Zhao, Lan, Feng Gao, Wang Wei, Xin Duan, Yuchen Zhang, Lina Zhu, and Xin Wang. "Poor-prognosis nasopharyngeal carcinoma as defined by a molecularly distinct subgroup and prediction by a miRNA expression signature." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 6056. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6056.

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6056 Background: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer, with diverse molecular characteristics and clinical outcomes. Our aim in this study is to dissect the molecular heterogeneity of NPC, followed by construction of a prognostic model for prediction of distant metastasis. Methods: For molecular subtyping of NPC using miRNA expression data, we selected 86 stage II (AJCC 7th Edition) NPC patients from GSE32960 as training cohort. The remaining 226 NPC patients from GSE32960 and 246 NPC patients from GSE70970 were used as two validation cohorts. Consensus clustering was employed for unsupervised classification of the training cohort. Classifier was built using support vector machine (SVM), and was validated in the two validation cohorts. Univariate and multivariate Cox regression analyses were employed for feature selection and constructing a prognostic model for predicting high-risk distant metastasis, respectively. Results: We identified three NPC subtypes (NPC1, 2, and 3) that are molecularly distinct and clinically relevant. NPC1 (~45%) is enriched for cell cycle related pathways, and patients classified to NPC1 have an intermediate survival; NPC3 (~19%) is enriched for immune related pathways, and has good clinical outcomes. More importantly, NPC2 (~36%) is associated with poor prognosis, and is characterized by upregulation of epithelial-mesenchymal transition (EMT). Out of the total 25 differentially expressed miRNAs in NPC2, miR-142, miR-26a, miR-141 and let-7i have significant prognostic power (p < 0.05), as determined by univariate Cox regression analysis. For identification of high-risk distant metastasis, we built a multivariate Cox regression model using the selected 4 miRNAs. Our model can robustly stratify NPC patients into high- and low- risk groups both in GSE32960 (HR 3.1, 95% CI 1.8-5.4, p = 1.2e-05) and GSE70970 (HR 2.2, 95% CI 1.1-4.5, p = 0.022) cohorts. Conclusions: We proposed for the first time that NPC can be stratified into three subtypes. Using a panel of 4 miRNAs, we established a prognostic model that can robustly stratify NPC patients into high- and low- risk groups of distant metastasis.

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Shen, X. X., D. Liang, J. Z. Wen, and P. Zhang. "Multiple Genome Alignments Facilitate Development of NPCL Markers: A Case Study of Tetrapod Phylogeny Focusing on the Position of Turtles." Molecular Biology and Evolution 28, no. 12 (June 16, 2011): 3237–52. http://dx.doi.org/10.1093/molbev/msr148.

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Tang, Yuyang, Ihid Carneiro Leao, Ebony M. Coleman, Robin Shepard Broughton, and James E. K. Hildreth. "Deficiency of Niemann-Pick Type C-1 Protein Impairs Release of Human Immunodeficiency Virus Type 1 and Results in Gag Accumulation in Late Endosomal/Lysosomal Compartments." Journal of Virology 83, no. 16 (May 27, 2009): 7982–95. http://dx.doi.org/10.1128/jvi.00259-09.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) relies on cholesterol-laden lipid raft membrane microdomains for entry into and egress out of susceptible cells. In the present study, we examine the need for intracellular cholesterol trafficking pathways with respect to HIV-1 biogenesis using Niemann-Pick type C-1 (NPC1)-deficient (NPCD) cells, wherein these pathways are severely compromised, causing massive accumulation of cholesterol in late endosomal/lysosomal (LE/L) compartments. We have found that induction of an NPC disease-like phenotype through treatment of various cell types with the commonly used hydrophobic amine drug U18666A resulted in profound suppression of HIV-1 release. Further, NPCD Epstein-Barr virus-transformed B lymphocytes and fibroblasts from patients with NPC disease infected with a CD4-independent strain of HIV-1 or transfected with an HIV-1 proviral clone, respectively, replicated HIV-1 poorly compared to normal cells. Infection of the NPCD fibroblasts with a vesicular stomatitis virus G-pseudotyped strain of HIV-1 produced similar results, suggesting a postentry block to HIV-1 replication in these cells. Examination of these cells using confocal microscopy showed an accumulation and stabilization of Gag in LE/L compartments. Additionally, normal HIV-1 production could be restored in NPCD cells upon expression of a functional NPC1 protein, and overexpression of NPC1 increased HIV-1 release. Taken together, our findings demonstrate that intact intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.

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Odongo, Laura, Kaneil K. Zadrozny, William E. Diehl, Jeremy Luban, Judith M. White, Barbie K. Ganser-Pornillos, Lukas K. Tamm, and Owen Pornillos. "Purification and structure of luminal domain C of human Niemann–Pick C1 protein." Acta Crystallographica Section F Structural Biology Communications 79, no. 2 (February 1, 2023): 45–50. http://dx.doi.org/10.1107/s2053230x23000705.

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Niemann–Pick C1 protein (NPC1) is a membrane protein that primarily resides in late endosomes and lysosomes, and plays an important role in cholesterol homeostasis in the cell. The second luminal domain of NPC1 (NPC1-C) serves as the intracellular receptor for Ebola and Marburg viruses. Here, the recombinant production of nonglycosylated and glycosylated NPC1-C and a new crystal form of the nonglycosylated protein are reported. The crystals belonged to space group P21 and diffracted to 2.3 Å resolution. The structure is similar to other reported structures of NPC1-C, with differences observed in the protruding loops when compared with NPC1-C in complex with Ebola virus glycoprotein or NPC2.

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Çakar, Nafiye Emel, and Hasan Önal. "Possible genotype-phenotype correlations in Niemann-Pick type C patients and miglustat treatment." Ideggyógyászati szemle 74, no. 3-4 (2021): 139–44. http://dx.doi.org/10.18071/isz.74.0139.

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Niemann-Pick type C is a rare lysosomal storage disease caused by impaired intracellular cholesterol transport. The autosomal recessive disease is caused by mutations in NPC1 or NPC2 genes. Clinical-laboratory features, genotype-phenotype correlation and miglustat treatment response of our patients diagnosed with early infantile Niemann-Pick type C were evaluated. In this article, four Niemann-Pick type C patients diagnosed in the early infantile period are presented. Common features of our patients were hepatomegaly, splenomegaly, cholestasis and retardation in motor development. Patients 1 and 2 are twins, with homozygous mutation c.2776G>A p.(Ala926Thr) in NPC1 gene and severe lung involvement. Lung involvement, which is mostly associated with NPC2 gene mutation in the literature, was severe in our patients and they died early. In patients 3 and 4, there were respectively c.2972del p.(Gln991Argfs*6) mutation in NPC1 gene and c.133C>T p.(Gln45*) homozygous mutation in NPC2 gene. In these two patients, improvement in neurological findings were observed with treatment of miglustat. In our twin patients, severe lung involvement was observed. Two of our four early infantile Niemann-Pick type C patients exhibited neurological gains with miglustat treatment.

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Wang, Zihan, Li Zhang, Yumin Hao, Wenjuan Dong, Yang Liu, Shengmei Song, Shaomin Shuang, Chuan Dong, and Xiaojuan Gong. "Ratiometric fluorescent sensors for sequential on-off-on determination of riboflavin, Ag+ and l-cysteine based on NPCl-doped carbon quantum dots." Analytica Chimica Acta 1144 (February 2021): 1–13. http://dx.doi.org/10.1016/j.aca.2020.11.054.

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Rakib, Tofazzal Md, Md Shafiqul Islam, Mohammad Mejbah Uddin, Mohammad Mahbubur Rahman, Akira Yabuki, Tetsushi Yamagami, Motoji Morozumi, et al. "Novel Mutation in the Feline NPC2 Gene in Cats with Niemann–Pick Disease." Animals 13, no. 11 (May 24, 2023): 1744. http://dx.doi.org/10.3390/ani13111744.

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Niemann–Pick disease (NP) type C is an autosomal, recessive, and inherited neurovisceral genetic disorder characterized by the accumulation of unesterified cholesterol and glycolipids in cellular lysosomes and late endosomes, with a wide spectrum of clinical phenotypes. This study aimed to determine the molecular genetic alterations in two cases of felines with NP in Japan, a Siamese cat in 1989 and a Japanese domestic (JD) cat in 1998. Sanger sequencing was performed on 25 exons of the feline NPC1 gene and 4 exons of the feline NPC2 gene, using genomic DNA extracted from paraffin-embedded tissue specimens. The sequenced exons were compared with reference sequences retrieved from the GenBank database. The identified mutations and alterations were then analyzed using different prediction algorithms. No pathogenic mutations were found in feline NPC1; however, c.376G>A (p.V126M) was identified as a pathogenic mutation in the NPC2 gene. The Siamese cat was found to be homozygous for this mutation. The JD cat was heterozygous for the same mutation, but no other exonic NPC2 mutation was found. Furthermore, the JD cat had a homozygous splice variant (c.364-4C>T) in the NPC2 gene, which is not known to be associated with this disease. The NPC2:c.376G>A (p.V126M) mutation is the second reported pathogenic mutation in the feline NPC2 gene that may be present in the Japanese cat population.

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Kubaski, Francyne, Alberto Burlina, Giulia Polo, Danilo Pereira, Zackary M. Herbst, Camilo Silva, Franciele B. Trapp, et al. "Experience of the NPC Brazil Network with a Comprehensive Program for the Screening and Diagnosis of Niemann-Pick Disease Type C." International Journal of Neonatal Screening 8, no. 3 (June 28, 2022): 39. http://dx.doi.org/10.3390/ijns8030039.

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Niemann-Pick disease type C (NPC) is a lysosomal disorder caused by impaired cholesterol metabolism. Levels of lysosphingomyelin 509 (LysoSM509) have been shown elevated in dried blood spots (DBS) of NPC and acid sphingomyelinase deficiency patients. In this study, we report our experience using a two-tier approach (1st tier is the quantification of lysoSM509 by ultra-performance liquid chromatography tandem mass spectrometry followed by the 2nd tier with next-generation sequencing of the NPC1 and NPC2 genes). DBS samples from 450 suspected patients were received by the NPC Brazil network. Of these, 33 samples had elevated levels of lysoSM509, and in 25 of them, variants classified as pathogenic, likely pathogenic, or of unknown significance were identified in the NPC1 or NPC2 genes by next-generation sequencing. The quantification of lysoSM509 in DBS as a first-tier test for the diagnosis of NPC followed by molecular analysis of the NPC1 and NPC2 genes almost doubled the detection rate when compared to the performance of chitotriosidase activity as a first-tier biomarker, and it could likely be increased with the addition of a third tier with MLPA of the two genes involved. This strategy seems suitable for the neonatal screening (NBS) of NPC if this disease is eventually adopted by NBS programs.

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D’Arcangelo, G., D. Grossi, M. Racaniello, A. Cardinale, A. Zaratti, S. Rufini, A. Cutarelli, V. Tancredi, D. Merlo, and C. Frank. "Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease." Neural Plasticity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/3830424.

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Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found thatin vivoMiglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia.

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Pfeffer, Suzanne R. "NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes." Journal of Biological Chemistry 294, no. 5 (February 1, 2019): 1706–9. http://dx.doi.org/10.1074/jbc.tm118.004165.

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Low-density lipoprotein particles are taken up by cells and delivered to the lysosome where their cholesterol esters are cleaved off by acid lipase. The released, free cholesterol is then exported from lysosomes for cellular needs or storage. This article summarizes recent advances in our understanding of the molecular basis of cholesterol export from lysosomes. Cholesterol export requires NPC intracellular cholesterol transporter 1 (NPC1) and NPC2, genetic mutations of which can cause Niemann–Pick type C disease, a disorder characterized by massive lysosomal accumulation of cholesterol and glycosphingolipids. Analysis of the NPC1 and NPC2 structures and biochemical properties, together with new structures of the related Patched (PTCH) protein, provides new clues to the mechanisms by which NPC proteins may function.

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Dixit, Sayali S., David E. Sleat, Ann M. Stock, and Peter Lobel. "Do mammalian NPC1 and NPC2 play a role in intestinal cholesterol absorption?" Biochemical Journal 408, no. 1 (October 29, 2007): 1–5. http://dx.doi.org/10.1042/bj20071167.

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NPC1L1 (Niemann–Pick C1-like 1), the pharmacological target of the cholesterol-uptake inhibitor ezetimibe, is a transporter localized on the brush border of enterocytes. Although this protein plays a key role in intestinal uptake of sterols, multiple molecular events that underlie intestinal cholesterol absorption have not been fully characterized. Two proteins that might be involved in this process are NPC1 and NPC2 (Niemann–Pick disease type C proteins 1 and 2), which function in the endosomal/lysosomal cholesterol egress pathway and whose deficiency results in NPC (Niemann–Pick type C) disease. The involvement of these proteins in intestinal cholesterol absorption was examined in mutant mice lacking either NPC1 or NPC2. Our data indicate that deficiencies in either protein do not have an effect on cholesterol uptake or absorption. This contrasts with recent results obtained for the fruitfly Drosophila melanogaster, which indicate that a deficiency of NPC1 (dNPC1a being its Drosophila homologue) leads to activation of an NPC1L1 (Drosophila homologue dNPC1b)-independent cholesterol uptake pathway, underscoring fundamental differences in mammalian and non-mammalian cholesterol metabolism.

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Argüello, Graciela, Elisa Balboa, Pablo J. Tapia, Juan Castro, María José Yañez, Pamela Mattar, Rodrigo Pulgar, and Silvana Zanlungo. "Genistein Activates Transcription Factor EB and Corrects Niemann–Pick C Phenotype." International Journal of Molecular Sciences 22, no. 8 (April 19, 2021): 4220. http://dx.doi.org/10.3390/ijms22084220.

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Niemann–Pick type C disease (NPCD) is a lysosomal storage disease (LSD) characterized by abnormal cholesterol accumulation in lysosomes, impaired autophagy flux, and lysosomal dysfunction. The activation of transcription factor EB (TFEB), a master lysosomal function regulator, reduces the accumulation of lysosomal substrates in LSDs where the degradative capacity of the cells is compromised. Genistein can pass the blood–brain barrier and activate TFEB. Hence, we investigated the effect of TFEB activation by genistein toward correcting the NPC phenotype. We show that genistein promotes TFEB translocation to the nucleus in HeLa TFEB-GFP, Huh7, and SHSY-5Y cells treated with U18666A and NPC1 patient fibroblasts. Genistein treatment improved lysosomal protein expression and autophagic flux, decreasing p62 levels and increasing those of the LC3-II in NPC1 patient fibroblasts. Genistein induced an increase in β-hexosaminidase activity in the culture media of NPC1 patient fibroblasts, suggesting an increase in lysosomal exocytosis, which correlated with a decrease in cholesterol accumulation after filipin staining, including cells treated with U18666A and NPC1 patient fibroblasts. These results support that genistein-mediated TFEB activation corrects pathological phenotypes in NPC models and substantiates the need for further studies on this isoflavonoid as a potential therapeutic agent to treat NPCD and other LSDs with neurological compromise.

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30

López-Pedrajas, D., M. Jiménez-Vázquez, A. M. Borreguero, F. J. Ramos, I. Garrido, J. F. Rodríguez, and M. Carmona. "Nanoencapsulated PCM slurries for the development of thermoregulating gypsums." Journal of Physics: Conference Series 2116, no. 1 (November 1, 2021): 012104. http://dx.doi.org/10.1088/1742-6596/2116/1/012104.

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Abstract Gypsums with improved thermal properties have been obtained using a thermoregulatory nanocapsulated slurry (NPCS) as additive. In order to determine the effects of the slurries in the gypsum, physical, mechanical and thermal properties of the different composite materials (gypsum – polystyrene nanoparticles (PS) or nanocapsules (NPCM)) have been studied. Concentrated slurries from polystyrene nanoparticles without (PSS) and with encapsulated phase change material (NPCS) have been synthesized. Firstly, gypsum blocks made of nanoparticles/hemihydrate with mass ratios ranging from 0.0 to 0.42 have been produced from PSS, in order to determine the optimal weight ratio with the best mechanical/physical characteristics. Then, the thermal gypsum block from NPCM/hemihydrate has been prepared at the selected weight ratio. Although PS and NPCM addition reduces the mechanical properties, all the developed materials satisfied the mechanical European regulation EN 13279-2 which limits the mechanical characteristics of gypsums composites. The gypsum composites with PS nanoparticles presented a reduction of the thermal conductivity, so these materials can be used as insulating material. The gypsum composite with NPCM/Hem = 0.3 had an improvement in the thermal storage capacity of 88.76 % and seems to be a good alternative for applying the thermal energy storage technology in buildings.

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Wheeler, Simon, Ralf Schmid, and Dan J. Sillence. "Lipid–Protein Interactions in Niemann–Pick Type C Disease: Insights from Molecular Modeling." International Journal of Molecular Sciences 20, no. 3 (February 7, 2019): 717. http://dx.doi.org/10.3390/ijms20030717.

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The accumulation of lipids in the late endosomes and lysosomes of Niemann–Pick type C disease (NPCD) cells is a consequence of the dysfunction of one protein (usually NPC1) but induces dysfunction in many proteins. We used molecular docking to propose (a) that NPC1 exports not just cholesterol, but also sphingosine, (b) that the cholesterol sensitivity of big potassium channel (BK) can be traced to a previously unappreciated site on the channel’s voltage sensor, (c) that transient receptor potential mucolipin 1 (TRPML1) inhibition by sphingomyelin is likely an indirect effect, and (d) that phosphoinositides are responsible for both the mislocalization of annexin A2 (AnxA2) and a soluble NSF (N-ethylmaleimide Sensitive Fusion) protein attachment receptor (SNARE) recycling defect. These results are set in the context of existing knowledge of NPCD to sketch an account of the endolysosomal pathology key to this disease.

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Erickson, Robert P. "Do GWAS and studies of heterozygotes for NPC1 and/or NPC2 explain why NPC disease cases are so rare?" Journal of Applied Genetics 59, no. 4 (September 13, 2018): 441–47. http://dx.doi.org/10.1007/s13353-018-0465-2.

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Colaco, Alexandria, María E. Fernández-Suárez, Dawn Shepherd, Lihi Gal, Chen Bibi, Silvia Chuartzman, Alan Diot, et al. "Unbiased yeast screens identify cellular pathways affected in Niemann–Pick disease type C." Life Science Alliance 3, no. 7 (June 2, 2020): e201800253. http://dx.doi.org/10.26508/lsa.201800253.

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Niemann–Pick disease type C (NPC) is a rare lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Mutations in the NPC1 gene lead to the majority of clinical cases (95%); however, the function of NPC1 remains unknown. To gain further insights into the biology of NPC1, we took advantage of the homology between the human NPC1 protein and its yeast orthologue, Niemann–Pick C–related protein 1 (Ncr1). We recreated the NCR1 mutant in yeast and performed screens to identify compensatory or redundant pathways that may be involved in NPC pathology, as well as proteins that were mislocalized in NCR1-deficient yeast. We also identified binding partners of the yeast Ncr1 orthologue. These screens identified several processes and pathways that may contribute to NPC pathogenesis. These included alterations in mitochondrial function, cytoskeleton organization, metal ion homeostasis, lipid trafficking, calcium signalling, and nutrient sensing. The mitochondrial and cytoskeletal abnormalities were validated in patient cells carrying mutations in NPC1, confirming their dysfunction in NPC disease.

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Li, Xiaochun, Feiran Lu, Michael N. Trinh, Philip Schmiege, Joachim Seemann, Jiawei Wang, and Günter Blobel. "3.3 Å structure of Niemann–Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport." Proceedings of the National Academy of Sciences 114, no. 34 (August 7, 2017): 9116–21. http://dx.doi.org/10.1073/pnas.1711716114.

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Niemann–Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann–Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Here, we report a crystal structure at 3.3 Å resolution of NPC1* (residues 314–1,278), which—in contrast to previous lower resolution structures—features the entire CTD well resolved. Notably, all eight cysteines of the CTD form four disulfide bonds, one of which (C909–C914) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD). Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution. Our mutagenesis experiments highlight the physiological relevance of the CTD–NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2. Additionally, this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease.

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Roszell, Blair R., Jian-Qin Tao, Kevin J. Yu, Shaohui Huang, and Sandra R. Bates. "Characterization of the Niemann-Pick C pathway in alveolar type II cells and lamellar bodies of the lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 9 (May 1, 2012): L919—L932. http://dx.doi.org/10.1152/ajplung.00383.2011.

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The Niemann-Pick C (NPC) pathway plays an essential role in the intracellular trafficking of cholesterol by facilitating the release of lipoprotein-derived sterol from the lumen of lysosomes. Regulation of cellular cholesterol homeostasis is of particular importance to lung alveolar type II cells because of the need for production of surfactant with an appropriate lipid composition. We performed microscopic and biochemical analysis of NPC proteins in isolated rat type II pneumocytes. NPC1 and NPC2 proteins were present in the lung, isolated type II cells in culture, and alveolar macrophages. The glycosylated and nonglycosylated forms of NPC1 were prominent in the lung and the lamellar body organelles. Immunocytochemical analysis of isolated type II pneumocytes showed localization of NPC1 to the limiting membrane of lamellar bodies. NPC2 and lysosomal acid lipase were found within these organelles, as confirmed by z-stack analysis of confocal images. All three proteins also were identified in small, lysosome-like vesicles. In the presence of serum, pharmacological inhibition of the NPC pathway with compound U18666A resulted in doubling of the cholesterol content of the type II cells. Filipin staining revealed a striking accumulation of cholesterol within lamellar bodies. Thus the NPC pathway functions to control cholesterol accumulation in lamellar bodies of type II pneumocytes and, thereby, may play a role in the regulation of surfactant cholesterol content.

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Dominko, Kristina, Ana Rastija, Sandra Sobocanec, Lea Vidatic, Sarah Meglaj, Andrea Lovincic Babic, Birgit Hutter-Paier, et al. "Impaired Retromer Function in Niemann-Pick Type C Disease Is Dependent on Intracellular Cholesterol Accumulation." International Journal of Molecular Sciences 22, no. 24 (December 9, 2021): 13256. http://dx.doi.org/10.3390/ijms222413256.

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Niemann-Pick type C disease (NPC) is a rare inherited neurodegenerative disorder characterized by an accumulation of intracellular cholesterol within late endosomes and lysosomes due to NPC1 or NPC2 dysfunction. In this work, we tested the hypothesis that retromer impairment may be involved in the pathogenesis of NPC and may contribute to increased amyloidogenic processing of APP and enhanced BACE1-mediated proteolysis observed in NPC disease. Using NPC1-null cells, primary mouse NPC1-deficient neurons and NPC1-deficient mice (BALB/cNctr-Npc1m1N), we show that retromer function is impaired in NPC. This is manifested by altered transport of the retromer core components Vps26, Vps35 and/or retromer receptor sorLA and by retromer accumulation in neuronal processes, such as within axonal swellings. Changes in retromer distribution in NPC1 mouse brains were observed already at the presymptomatic stage (at 4-weeks of age), indicating that the retromer defect occurs early in the course of NPC disease and may contribute to downstream pathological processes. Furthermore, we show that cholesterol depletion in NPC1-null cells and in NPC1 mouse brains reverts retromer dysfunction, suggesting that retromer impairment in NPC is mechanistically dependent on cholesterol accumulation. Thus, we characterized retromer dysfunction in NPC and propose that the rescue of retromer impairment may represent a novel therapeutic approach against NPC.

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Stephney, Gloria, and Steven Walkley. "Ultrastructural Similarity of Storage Bodies in Neurons Lacking NPC1, NPC2, or Both Proteins Suggest NPC1-NPC2 Molecular Co-operativity in Lipid Trafficking." Microscopy and Microanalysis 10, S02 (August 2004): 1468–69. http://dx.doi.org/10.1017/s1431927604882643.

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Fukaura, Madoka, Yoichi Ishitsuka, Seiichi Shirakawa, Naoki Ushihama, Yusei Yamada, Yuki Kondo, Toru Takeo, et al. "Intracerebroventricular Treatment with 2-Hydroxypropyl-β-Cyclodextrin Decreased Cerebellar and Hepatic Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Expression in Niemann–Pick Disease Type C Model Mice." International Journal of Molecular Sciences 22, no. 1 (January 5, 2021): 452. http://dx.doi.org/10.3390/ijms22010452.

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Niemann–Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the NPC1 or NPC2 gene. It is characterized by abnormality of cellular cholesterol trafficking with severe neuronal and hepatic injury. In this study, we investigated the potential of glycoprotein nonmetastatic melanoma protein B (GPNMB) to act as a biomarker reflecting the therapeutic effect of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in an NPC mouse model. We measured serum, brain, and liver expression levels of GPNMB, and evaluated their therapeutic effects on NPC manifestations in the brain and liver after the intracerebroventricular administration of HP-β-CD in Npc1 gene-deficient (Npc1−/−) mice. Intracerebroventricular HP-β-CD inhibited cerebellar Purkinje cell damage in Npc1−/− mice and significantly reduced serum and cerebellar GPNMB levels. Interestingly, we also observed that the intracerebral administration significantly reduced hepatic GPNMB expression and elevated serum ALT in Npc1−/− mice. Repeated doses of intracerebroventricular HP-β-CD (30 mg/kg, started at 4 weeks of age and repeated every 2 weeks) drastically extended the lifespan of Npc1−/− mice compared with saline treatment. In summary, our results suggest that GPNMB level in serum is a potential biomarker for evaluating the attenuation of NPC pathophysiology by intracerebroventricular HP-β-CD treatment.

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Frolov, Andrey, Kalpana Srivastava, Dorit Daphna-Iken, Linton M. Traub, Jean E. Schaffer, and Daniel S. Ory. "Cholesterol Overload Promotes Morphogenesis of a Niemann-Pick C (NPC)-like Compartment Independent of Inhibition of NPC1 or HE1/NPC2 Function." Journal of Biological Chemistry 276, no. 49 (September 24, 2001): 46414–21. http://dx.doi.org/10.1074/jbc.m108099200.

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Yu, Daozhan, Manju Swaroop, Mengqiao Wang, Ulrich Baxa, Rongze Yang, Yiping Yan, Turhan Coksaygan, et al. "Niemann–Pick Disease Type C." Journal of Biomolecular Screening 19, no. 8 (June 6, 2014): 1164–73. http://dx.doi.org/10.1177/1087057114537378.

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Niemann–Pick disease type C (NPC) is a rare neurodegenerative disorder caused by recessive mutations in the NPC1 or NPC2 gene that result in lysosomal accumulation of unesterified cholesterol in patient cells. Patient fibroblasts have been used for evaluation of compound efficacy, although neuronal degeneration is the hallmark of NPC disease. Here, we report the application of human NPC1 neural stem cells as a cell-based disease model to evaluate nine compounds that have been reported to be efficacious in the NPC1 fibroblasts and mouse models. These cells are differentiated from NPC1 induced pluripotent stem cells and exhibit a phenotype of lysosomal cholesterol accumulation. Treatment of these cells with hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, and δ-tocopherol significantly ameliorated the lysosomal cholesterol accumulation. Combined treatment with cyclodextrin and δ-tocopherol shows an additive or synergistic effect that otherwise requires 10-fold higher concentration of cyclodextrin alone. In addition, we found that hydroxypropyl-β-cyclodextrin is much more potent and efficacious in the NPC1 neural stem cells compared to the NPC1 fibroblasts. Miglustat, suberoylanilide hydroxamic acid, curcumin, lovastatin, pravastatin, and rapamycin did not, however, have significant effects in these cells. The results demonstrate that patient-derived NPC1 neural stem cells can be used as a model system for evaluation of drug efficacy and study of disease pathogenesis.

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Newton, Jason, Elisa N. D. Palladino, Cynthia Weigel, Michael Maceyka, Markus H. Gräler, Can E. Senkal, Ricardo D. Enriz, et al. "Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation." Journal of Biological Chemistry 295, no. 27 (May 8, 2020): 9121–33. http://dx.doi.org/10.1074/jbc.ra120.012659.

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Niemann–Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism.

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Maxfield, Frederick R., David B. Iaea, and Nina H. Pipalia. "Role of STARD4 and NPC1 in intracellular sterol transport." Biochemistry and Cell Biology 94, no. 6 (December 2016): 499–506. http://dx.doi.org/10.1139/bcb-2015-0154.

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Cholesterol plays an important role in determining the biophysical properties of membranes in mammalian cells, and the concentration of cholesterol in membranes is tightly regulated. Cholesterol moves among membrane organelles by a combination of vesicular and nonvesicular transport pathways, but the details of these transport pathways are not well understood. In this review, we discuss the mechanisms for nonvesicular sterol transport with an emphasis on the role of STARD4, a small, soluble, cytoplasmic sterol transport protein. STARD4 can rapidly equilibrate sterol between membranes, especially membranes with anionic lipid headgroups. We also discuss the sterol transport in late endosomes and lysosomes, which is mediated by a soluble protein, NPC2, and a membrane protein, NPC1. Homozygous mutations in these proteins lead to a lysosomal lipid storage disorder, Niemann–Pick disease type C. Many of the disease-causing mutations in NPC1 are associated with degradation of the mutant NPC1 proteins in the endoplasmic reticulum. Several histone deacetylase inhibitors have been found to rescue the premature degradation of the mutant NPC1 proteins, and one of these is now in a small clinical trial.

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Van Hoecke, Lien, Caroline Van Cauwenberghe, Verena Börger, Arnout Bruggeman, Jonas Castelein, Griet Van Imschoot, Elien Van Wonterghem, et al. "Anti-Inflammatory Mesenchymal Stromal Cell-Derived Extracellular Vesicles Improve Pathology in Niemann–Pick Type C Disease." Biomedicines 9, no. 12 (December 8, 2021): 1864. http://dx.doi.org/10.3390/biomedicines9121864.

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Niemann–Pick type C (NPC) disease is a rare neurovisceral lipid storage disease with progressive neurodegeneration, leading to premature death. The disease is caused by loss-of-function mutations either in the NPC1 or NPC2 gene which results in lipid accumulation in the late endosomes and lysosomes. The involved disease mechanisms are still incompletely understood, making the design of a rational treatment very difficult. Since the disease is characterized by peripheral inflammation and neuroinflammation and it is shown that extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs) provide immunomodulatory capacities, we tested the potential of MSC-EV preparations to alter NPC1 disease pathology. Here, we show that the administration of an MSC-EV preparation with in vitro and in vivo confirmed immune modulatory capabilities is able to reduce the inflammatory state of peripheral organs and different brain regions of NPC1-diseased mice almost to normal levels. Moreover, a reduction of foamy cells in different peripheral organs was observed upon MSC-EV treatment of NPC1−/− mice. Lastly, the treatment was able to decrease microgliosis and astrogliosis, typical features of NPC1 patients that lead to neurodegeneration. Altogether, our results reveal the therapeutic potential of MSC-EVs as treatment for the genetic neurovisceral lipid storage disease NPC, thereby counteracting both central and peripheral features.

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Wen, Qin, Xuexin Yuan, Qiqi Zhou, Hai-Jian Yang, Qingqing Jiang, Juncheng Hu, and Cun-Yue Guo. "Solvent-Free Coupling Reaction of Carbon Dioxide and Epoxides Catalyzed by Quaternary Ammonium Functionalized Schiff Base Metal Complexes under Mild Conditions." Materials 16, no. 4 (February 16, 2023): 1646. http://dx.doi.org/10.3390/ma16041646.

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A series of bifunctional Schiff base metal catalysts (Zn-NPClR, Zn-NPXH, and M-NPClH) with two quaternary ammonium groups were prepared for carbon dioxide (CO2) and epoxide coupling reactions. The effects of the reaction variables on the catalytic activity were systematically investigated, and the optimal reaction conditions (120 °C, 1 MPa CO2, 3 h) were screened. The performances of different metal-centered catalysts were evaluated, and Co-NPClH showed excellent activity. This kind of bifunctional catalyst has a wide range of substrate applicability, excellent stability, and can be reused for more than five runs. A relatively high TOF could reach up to 1416 h−1 with Zn-NPClH as catalyst by adjusting reaction factors. In addition, the kinetic study of the coupling reaction catalyzed by three catalysts (Zn, Co, and Ni) was carried out to obtain the activation energy (Ea) for the formation of cyclic carbonates. Finally, a possible mechanism for this cyclization reaction was proposed.

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Balboa, Elisa, Tamara Marín, Juan Esteban Oyarzún, Pablo S. Contreras, Robert Hardt, Thea van den Bosch, Alejandra R. Alvarez, et al. "Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage." Cells 10, no. 8 (August 21, 2021): 2159. http://dx.doi.org/10.3390/cells10082159.

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Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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Essawi, Mona L., Asmaa F. Abdel-aleem, Mohamed A. Badawy, Maha S. Zaki, Magda F. Mohamed, Heba A. Hassan, and Ekram M. Fateen. "Variants in the NPC1 Gene in Egyptian Patients with Niemann-Pick Type C." Open Access Macedonian Journal of Medical Sciences 8, A (May 5, 2020): 134–45. http://dx.doi.org/10.3889/oamjms.2020.4626.

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BACKGROUND: Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, progressive neuro-visceraldisease caused by biallelic mutations in either NPC1gene (95% of cases) or NPC2 gene. AIM: This caseseries study aimed at the molecular analysis of certain hot spots of NPC1 genein NPC Egyptian patients. METHODS: The study included 15 unrelated NPC patients and selected parents,as well as20 healthy controls of matched sex and age. Clinical investigations were performed according to well established clinical criteria. Assessment of the chitotriosidase level, as an initial screening tool for NPC, was done in all cases. Polymerase chain reaction amplification of NPC1 exons (17–25) encountering the hotspot residues (855–1098 and1038–1253) was carried out followed by direct sequencingfor mutational analysis. RESULTS: All includedpatients with mainly neurovisceral involvement were characterized. The onset of the disease varied from early-infantile (58.3%) to late-infantile (26.7%) and juvenile-onset (6.7%). Ahigh chitotriosidase level wasobservedin all patients. Molecular analysis of NPC1 (exons 17–25) confirmed 15 mutant alleles out of 30 studied ones. They included two novel homozygous missense variants (p.Ser1169Arg and p.Ser1197Phe) and previously reportedfour mutations (p.Arg958*, p.Gly910Ser, p.Ala927Glyfs*38, and andp.Cys1011*). CONCLUSION: The two studied amino acid residues (855–1098 and 1038–1253) could beconsidered aspotential hotspot regions in NPC1 Egyptian patients.

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Feng, Xiao, Claudia Cozma, Supansa Pantoom, Christina Hund, Katharina Iwanov, Janine Petters, Christin Völkner, et al. "Determination of the Pathological Features of NPC1 Variants in a Cellular Complementation Test." International Journal of Molecular Sciences 20, no. 20 (October 19, 2019): 5185. http://dx.doi.org/10.3390/ijms20205185.

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Niemann-Pick Type C (NP-C) is a rare disorder of lipid metabolism caused by mutations within the NPC1 and NPC2 genes. NP-C is a neurovisceral disease leading to a heterogeneous, multisystemic spectrum of symptoms in those affected. Until now, there is no investigative tool to demonstrate the significance of single variants within the NPC genes. Hence, the aim of the study was to establish a test that allows for an objective assessment of the pathological potential of NPC1 gene variants. Chinese hamster ovary cells defective in the NPC1 gene accumulate cholesterol in lysosomal storage organelles. The cells were transfected with NPC1-GFP plasmid vectors carrying distinct sequence variants. Filipin staining was used to test for complementation of the phenotype. The known variant p.Ile1061Thr showed a significantly impaired cholesterol clearance after 12 and 24 h compared to the wild type. Among the investigated variants, p.Ser954Leu and p.Glu1273Lys showed decelerated cholesterol clearance as well. The remaining variants p.Gln60His, p.Val494Met, and p.Ile787Val showed a cholesterol clearance indistinguishable from wild type. Further, p.Ile1061Thr acquired an enhanced clearance ability upon 25-hydroxycholesterol treatment. We conclude that the variants that caused an abnormal clearance phenotype are highly likely to be of clinical relevance. Moreover, we present a system that can be utilized to screen for new drugs.

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Estiu, Guillermina, Nazir Khatri, and Olaf Wiest. "Computational Studies of the Cholesterol Transport between NPC2 and the N-Terminal Domain of NPC1 (NPC1(NTD))." Biochemistry 52, no. 39 (September 19, 2013): 6879–91. http://dx.doi.org/10.1021/bi4005478.

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Walkley, Steven U., and Kinuko Suzuki. "Consequences of NPC1 and NPC2 loss of function in mammalian neurons." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1685, no. 1-3 (October 2004): 48–62. http://dx.doi.org/10.1016/j.bbalip.2004.08.011.

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Lopez, Adam M., Ryan D. Jones, Joyce J. Repa, and Stephen D. Turley. "Niemann-Pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function." American Journal of Physiology-Gastrointestinal and Liver Physiology 315, no. 4 (October 1, 2018): G454—G463. http://dx.doi.org/10.1152/ajpgi.00124.2018.

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Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase (SOAT) 1 or SOAT2 in various cell types and lecithin cholesterol acyltransferase in plasma. Esterified cholesterol and triacylglycerol contained in lipoproteins cleared from the circulation via receptor-mediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C (NPC) 2 and NPC 1, unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease, which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7-wk-old mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1:SOAT2 double knockouts, compared with their littermates lacking only NPC1, had 20% less liver mass, 28% lower hepatic UC concentrations, and plasma alanine aminotransferase and aspartate aminotransferase activities that were decreased by 48% and 36%, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency. NEW & NOTEWORTHY In Niemann-Pick type C1 (NPC1) disease, the entrapment of unesterified cholesterol (UC) in the endosomal/lysosomal compartment of all cells causes multiorgan disease, including neurodegeneration, pulmonary dysfunction, and liver failure. Some of this sequestered UC entered cells initially in the esterified form. When sterol O-acyltransferase 2, a cholesterol esterifying enzyme present in enterocytes and hepatocytes, is eliminated in NPC1-deficient mice, there is a reduction in their hepatomegaly, hepatic UC content, and cellular injury.

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Journal articles on the topic 'NPCL'

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