Startseite Model construction of Niemann-Pick type C disease in zebrafish
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

Model construction of Niemann-Pick type C disease in zebrafish

  • Yusheng Lin , Xiaolian Cai , Guiping Wang , Gang Ouyang und Hong Cao EMAIL logo
Veröffentlicht/Copyright: 20. Juni 2018
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 399 Heft 8

Abstract

Niemann-Pick type C disease (NPC) is a rare human disease, with limited effective treatment options. Most cases of NPC disease are associated with inactivating mutations of the NPC1 gene. However, cellular and molecular mechanisms responsible for the NPC1 pathogenesis remain poorly defined. This is partly due to the lack of a suitable animal model to monitor the disease progression. In this study, we used CRISPR to construct an NPC1−/− zebrafish model, which faithfully reproduced the cardinal pathological features of this disease. In contrast to the wild type (WT), the deletion of NPC1 alone caused significant hepatosplenomegaly, ataxia, Purkinje cell death, increased lipid storage, infertility and reduced body length and life span. Most of the NPC1−/− zebrafish died within the first month post fertilization, while the remaining specimens developed slower than the WT and died before reaching 8 months of age. Filipin-stained hepatocytes of the NPC1−/− zebrafish were clear, indicating abnormal accumulation of unesterified cholesterol. Lipid profiling showed a significant difference between NPC1−/− and WT zebrafish. An obvious accumulation of seven sphingolipids was detected in livers of NPC1−/− zebrafish. In summary, our results provide a valuable model system that could identify promising therapeutic targets and treatments for the NPC disease.

Keywords: cholesterol; CRISPR/Cas9; NPC1; zebrafish

Acknowledgements

The authors thank Dr. Wei Dong and Dr. Huifang Liang (Tongji Medical College, Huazhong University of Science and Technology), Dr. Wuhan Xiao (Institute of Hydrobiology, Chinese Academy of Sciences) for assistance with the project design and many advices for manuscript preparation. This work was supported by the State Key Laboratory of Freshwater Ecology and Biotechnology (2012FB04).

References

Cao, H., Zhou, L., Zhang, Y.Z., Wei, Q.W., Chen, X.H., and Gui, J.F. (2009). Molecular characterization of Chinese sturgeon gonadotropins and cellular distribution in pituitaries of mature and immature individuals. Mol. Cell Endocrinol. 303, 34–42.10.1016/j.mce.2009.01.015Suche in Google Scholar PubMed

Chan, R.B., Oliveira, T.G., Cortes, E.P., Honig, L.S., Duff, K.E., Small, S.A., Wenk, M.R., Shui, G., and Paolo, G.D. (2012). Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. J. Biol. Chem. 287, 2678–2688.10.1074/jbc.M111.274142Suche in Google Scholar PubMed PubMed Central

Chang, N., Sun, C., Gao, L., Zhu, D., Xu, X., Zhu, X., Xiong, J.W., and Xi, J.J. (2013). Genome editing with RNA-guided Cas9 nuclease in zebrafish embryos. Cell Res. 23, 465–472.10.1038/cr.2013.45Suche in Google Scholar PubMed PubMed Central

Davies, J.P. and Ioannou, Y.A. (2000). Topological analysis of Niemann-Pick C1 protein reveals that the membrane orientation of the putative sterol-sensing domain is identical to those of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein cleavage-activating protein. J. Biol. Chem. 275, 24367–24374.10.1074/jbc.M002184200Suche in Google Scholar PubMed

Davison, J.M., Park, S.W., Rhee, J.M., and Leach, S.D. (2008). Characterization of Kras-mediated pancreatic tumorigenesis in zebrafish. Method Enzymol. 438, 391–417.10.1016/S0076-6879(07)38027-0Suche in Google Scholar PubMed

Fan, M., Sidhu, R., Fujiwara, H., Tortelli, B., Zhang, J., Davidson, C., Walkley, S.U., Bagel, J.H., Vite, C., Yanjanin, N.M., et al. (2013). Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling. J. Lipid Res. 54, 2800–2814.10.1194/jlr.M040618Suche in Google Scholar PubMed PubMed Central

Greer, W.L., Donson, M.J., Girouard, G.S., Byers, D.M., Riddell, D.C., and Neumann, P.E. (1999). Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain. Am. J. Hum. Genet. 65, 1252–1260.10.1086/302620Suche in Google Scholar PubMed PubMed Central

Hall, C., Flores, M.V., Storm, T., Crosier, K., and Crosier, P. (2007). The zebrafish lysozyme C promoter drives myeloid-specific expression in transgenic fish. BMC Dev. Biol. 7, 42.10.1186/1471-213X-7-42Suche in Google Scholar PubMed PubMed Central

Higaki, K., Almanzar-Paramio, D., and Sturley, S. (2004). Metazoan and microbial models of Niemann-Pick type C disease. Biochim. Biophys. Acta 1685, 38–47.10.1016/j.bbalip.2004.08.010Suche in Google Scholar PubMed

Huang, X., Suyama, K., Buchanan, J., Zhu, A.J., and Scott, M.P. (2005). A drosophila model of the Niemann-Pick type C lysosome storage disease: dnpc1a is required for molting and sterol homeostasis. Development 132, 5115–5124.10.1242/dev.02079Suche in Google Scholar PubMed

Karten, B., Vance, D.E., Campenot, R.B., and Vance, J.E. (2003). Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1 deficient neurons. J. Biol. Chem. 278, 4168–4175.10.1074/jbc.M205406200Suche in Google Scholar PubMed

Kuwamura, M., Awakura, T., Shimada, A., Umemura, T., Kagota, K., Kawamura, N., and Naiki, M. (1993). Type C Niemann-Pick disease in a boxer dog. Acta Neuropathol. 85, 345–348.10.1007/BF00227733Suche in Google Scholar PubMed

Langenau, D.M., Keefe, M.D., Storer, N.Y., Guyon, J.R., Kutok, J.L., Le, X.N., Goessling, W., Neuberg, D.S., Kunkel, L.M., and Zon, L.I. (2007). Effects of RAS on the genesis of embryonal rhabdomyosarcoma. Genes. Dev. 21, 1382–1395.10.1101/gad.1545007Suche in Google Scholar PubMed PubMed Central

Li, H., Repa, J.J., Valasek, M.A., and Dietschy, J.M. (2005). Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease. J. Neuropath. Exp. Neur. 64, 323–333.10.1093/jnen/64.4.323Suche in Google Scholar PubMed

Li, Z., Huang, X., Zhan, H., Zeng, Z., Li, C., Spitsbergen, J.M., Meierjohann, S., Schartl, M., and Gong, Z. (2012). Inducible and repressable oncogene-addicted hepatocellular carcinoma in Tet-on xmrk transgenic zebrafish. J. Hepatol. 56, 419–425.10.1016/j.jhep.2011.07.025Suche in Google Scholar PubMed

Liu, D., Wang, Z.X., Xiao, A., Zhang, Y.T., Li, W.Y., Zu, Y., Yao, S.H., Lin, S., and Zhang, B. (2014). Efficient gene targeting in zebrafish mediated by a zebrafish-codon-optimized cas9 and evaluation of off-targeting effect. J. Genet. Genomics. 41, 43–46.10.1016/j.jgg.2013.11.004Suche in Google Scholar PubMed

Loftus, S.K., Morris, J.A., Carstea, E.D., Gu, J.Z., Cummings, C., Brown, A., Ellison, J., Ohno, K., Rosenfeld, M.A., Tagle, D.A., et al. (1997). Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277, 232–235.10.1126/science.277.5323.232Suche in Google Scholar PubMed

Louwette, S., Régal, L., Wittevrongel, C., Thys, C., Vandeweeghde, G., Decuyper, E., Leemans, P., Vos, R.D., Geet, C.V., Jaeken, J., et al. (2013). NPC1 defect results in abnormal platelet formation and function: studies in Niemann–Pick disease type C1 patients and zebrafish. Hum. Mol. Genet. 22, 61–73.10.1093/hmg/dds401Suche in Google Scholar PubMed

Lowenthal, A.C., Cummings, J.F., Wenger, D.A., Thrall, M.A., Wood, P.A., and Lahunta, A.D. (1990). Feline sphingomyelinosis resembling Niemann–Pick disease type C. Acta Neuropathol. 81, 189–197.10.1007/BF00334507Suche in Google Scholar PubMed

Millat, G., Marcais, C., Tomasetto, C., Chikh, K., Fensom, A.H., Harzer, K., Wenger, D.A., Ohno, K., and Vanier, M.T. (2001). Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Am. J. Hum. Genet. 68, 1373–1385.10.1086/320606Suche in Google Scholar PubMed PubMed Central

Ota, S., Hisano, Y., Muraki, M., Hoshijima, K., Dahlem, T.J., Grunwald, D.J., Okada, Y., and Kawahara, A. (2013). Efficient identification of TALEN-mediated genome modifications using heteroduplex mobility assays. Genes. Cells 18, 450–458.10.1111/gtc.12050Suche in Google Scholar PubMed PubMed Central

Park, W.D., O’Brien, J.F., Lundquist, P.A., Kraft, D.L., Vockley, C.W., Karnes, P.S., Patterson, M.C., and Snow, K. (2003). Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum. Mutat. 22, 313–325.10.1002/humu.10255Suche in Google Scholar PubMed

Patton, E.E., Widlund, H.R., Kutok, J.L., Kopani, K.R., Amatruda, J.F., Murphey, R.D., Berghmans, S., Mayhall, E.A., Traver, D., Fletcher, C.D.M., et al. (2005). BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr. Biol. 15, 249–254.10.1016/j.cub.2005.01.031Suche in Google Scholar PubMed

Paul, C.A., Boegle, A.K., and Maue, R.A. (2004). Before the loss: Neuronal dysfunction in Niemann-Pick type C disease. Biochim. Biophys. Acta Biomembr. 1685, 63–76.10.1016/j.bbalip.2004.08.012Suche in Google Scholar PubMed

Praggastis, M., Tortelli, B., Zhang, J., Fujiwara, H., Sidhu, R., Chacko, A., Chen, Z.J., Chung, C., Lieberman, A.P., Sikora, J., et al. (2015). A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele. J. Neurosci. 35, 8091–8106.10.1523/JNEUROSCI.4173-14.2015Suche in Google Scholar PubMed PubMed Central

Schiffer, N.W., Broadley, S.A., Hirschberger, T., Tavan, P., Kretzschmar, H.A., Giese, A., Haass, C., Hartl, F.U., and Schmid, B. (2007). Identification of anti-prion compounds asefficient inhibitors of polyglutamine protein aggregation in a zebrafish model. J. Biol. Chem. 282, 9195–9203.10.1074/jbc.M607865200Suche in Google Scholar PubMed

Schwend, T., Loucks, E.J., Snyder, D., and Ahigren, S.C. (2011). Requirement of Npc1 and availability of cholesterol for early embryonic cell movements in zebrafish. J. Lipid Res. 52, 1328–1344.10.1194/jlr.M012377Suche in Google Scholar PubMed PubMed Central

Sévin, M., Lesca, G., Baumann, N., Millat, G., Lyon-Cane, O., Vanier, M.T., and Sedel, F. (2007). The adult form of Niemann–Pick disease type C. Brain 130, 120–133.10.1093/brain/awl260Suche in Google Scholar PubMed

Sym, M., Basson, M., and Johnson, C. (1999). A model for Niemann–Pick type C disease in the nematode Caenorhabditis elegans. Curr. Biol. 10, 527–530.10.1016/S0960-9822(00)00468-1Suche in Google Scholar PubMed

Tomasiewicz, H.G., Flaherty, D.B., Soria, J.P., and Wood, J.G. (2002). Transgenic zebrafish model of neurodegeneration. J. Neurosci. Res. 70, 734–745.10.1002/jnr.10451Suche in Google Scholar PubMed

Vanier, M.T. (2010). Niemann–Pick disease type C. Orphanet J. Rare Dis. 5, 16.10.1002/9781118514672.ch11Suche in Google Scholar

Walkley, S. and Suzuki, K. (2004). Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim. Biophys. Acta Biomembr. 1685, 48–62.10.1016/j.bbalip.2004.08.011Suche in Google Scholar PubMed

Wang, J., Leng, X.Q., Wang, G.P., Wan, X.Y., and Cao, H. (2017). The construction of intrahepatic cholangiocarcinoma model in zebrafish. Sci. Rep. 7, 13419.10.1038/s41598-017-13815-0Suche in Google Scholar PubMed PubMed Central

Wassif, C.A., Cross, J.L., Iben, J., Sanchez-Pulido, L., Couqnoux, A., Platt, F.M., Ory, D.S., Ponting, C.P., Bailey-Wilson, J.E., Biesecker, L.G., et al. (2016). High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets. Genet. Med. 18, 41–48.10.1038/gim.2015.25Suche in Google Scholar PubMed PubMed Central

Whitesell, T.R., Kennedy, R.M., Carter, A.D., Rollins, E.L., Georgijevic, S., Santoro, M.M., and Childs, S.J. (2014). An α-smooth muscle actin (acta2/αsma) zebrafish transgenic line marking vascular mural cells and visceral smooth muscle cells. PLoS One 9, e90590.10.1371/journal.pone.0090590Suche in Google Scholar PubMed PubMed Central

Yamamoto, T., Ninomiya, H., Matsumoto, M., Ohta, Y., Nanba, E., Tsutsumi, Y., Yamakawa, K., Millat, G., Vanier, M.T., Pentchev, P.G., et al. (2000). Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts. J. Med. Genet. 37, 707–711.10.1136/jmg.37.9.707Suche in Google Scholar PubMed PubMed Central

Supplementary Material:

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0118).

Received: 2018-01-15
Accepted: 2018-05-14
Published Online: 2018-06-20
Published in Print: 2018-07-26

©2018 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Exploratory cell dynamics: a sense of touch for cells?
  4. Kallikrein-related peptidases and associated microRNAs as promising prognostic biomarkers in gastrointestinal malignancies
  5. Sphingolipid metabolism – an ambiguous regulator of autophagy in the brain
  6. Minireview
  7. Insulin-like signaling within and beyond metazoans
  8. Research Articles/Short Communications
  9. Genes and Nucleic Acids
  10. Oxidation of 1-N2-etheno-2′-deoxyguanosine by singlet molecular oxygen results in 2′-deoxyguanosine: a pathway to remove exocyclic DNA damage?
  11. Protein Structure and Function
  12. Novel approach to quorum quenching: rational design of antibacterials in combination with hexahistidine-tagged organophosphorus hydrolase
  13. The forkhead domain hinge-loop plays a pivotal role in DNA binding and transcriptional activity of FOXP2
  14. New clues into the self-assembly of Vmh2, a basidiomycota class I hydrophobin
  15. Membranes, Lipids, Glycobiology
  16. Model construction of Niemann-Pick type C disease in zebrafish
  17. Cell Biology and Signaling
  18. Upregulation of Twist is involved in Gli1 induced migration and invasion of hepatocarcinoma cells
https://doi.org/10.1515/hsz-2018-0118
Schlagwörter für diesen Artikel
cholesterol; CRISPR/Cas9; NPC1; zebrafish

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Exploratory cell dynamics: a sense of touch for cells?
  4. Kallikrein-related peptidases and associated microRNAs as promising prognostic biomarkers in gastrointestinal malignancies
  5. Sphingolipid metabolism – an ambiguous regulator of autophagy in the brain
  6. Minireview
  7. Insulin-like signaling within and beyond metazoans
  8. Research Articles/Short Communications
  9. Genes and Nucleic Acids
  10. Oxidation of 1-N2-etheno-2′-deoxyguanosine by singlet molecular oxygen results in 2′-deoxyguanosine: a pathway to remove exocyclic DNA damage?
  11. Protein Structure and Function
  12. Novel approach to quorum quenching: rational design of antibacterials in combination with hexahistidine-tagged organophosphorus hydrolase
  13. The forkhead domain hinge-loop plays a pivotal role in DNA binding and transcriptional activity of FOXP2
  14. New clues into the self-assembly of Vmh2, a basidiomycota class I hydrophobin
  15. Membranes, Lipids, Glycobiology
  16. Model construction of Niemann-Pick type C disease in zebrafish
  17. Cell Biology and Signaling
  18. Upregulation of Twist is involved in Gli1 induced migration and invasion of hepatocarcinoma cells
Jetzt anmelden und 20% sparen
Institutioneller Zugang
Wie funktioniert Authentifizierung?
Haben Sie eine Idee, wie wir unsere Website verbessern können?
Bitte schreiben Sie uns.
© 2025 De Gruyter Brill
Heruntergeladen am 2.10.2025 von https://www.degruyterbrill.com/document/doi/10.1515/hsz-2018-0118/html
Button zum nach oben scrollen