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Pathological manifestations of Farber disease in a new mouse model

  • Nadine Beckmann , Stephanie Kadow , Fabian Schumacher , Joachim R. Göthert , Stefanie Kesper , Annette Draeger , Walter J. Schulz-Schaeffer , Jiang Wang , Jan U. Becker , Melanie Kramer , Claudine Kühn , Burkhard Kleuser , Katrin Anne Becker , Erich Gulbins and Alexander Carpinteiro EMAIL logo
Published/Copyright: June 21, 2018
Biological Chemistry
From the journal Biological Chemistry Volume 399 Issue 10

Abstract

Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1tmEx1 mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.

Keywords: acid ceramidase; ceramide; Farber disease; lysosomal storage disorders

Funding source: DFG

Award Identifier / Grant number: GU 335-35/1

Funding statement: This work was supported by DFG grant GU 335-35/1 to EG and GRK 2098 (Funder Id: 10.13039/501100001659) to KBF and EG.

Acknowledgments

We thank S. Keitsch, C. Müller and S. Harde for their excellent help with the animal experiments and D. Herrmann for his excellent technical assistance with the LC-MS/MS analyses. We thank Beat Haenni for the electron microscopical preparations. Electron micrographs were acquired on equipment supported by the Microscopy Imaging Center (MIC) of the University of Bern.

  1. Conflict of interest statement: The authors declare that they have no conflict of interest.

References

Alayoubi, A.M., Wang, J.C., Au, B.C., Carpentier, S., Garcia, V., Dworski, S., El-Ghamrasni, S., Kirouac, K.N., Exertier, M.J., Xiong, Z.J., et al. (2013). Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Mol. Med. 5, 827–842.10.1002/emmm.201202301Search in Google Scholar

Antonarakis, S.E., Valle, D., Moser, H.W., Moser, A., Qualman, S.J., and Zinkham, W.H. (1984). Phenotypic variability in siblings with Farber disease. J. Pediatr. 104, 406–409.10.1016/S0022-3476(84)81106-3Search in Google Scholar

Bao, X.H., Tian, J.M., Ji, T.Y., and Chang, X.Z. (2017). [A case report of childhood Farber’s disease and literature review]. Zhonghua Er Ke Za Zhi. 55, 54–58.Search in Google Scholar

Ben-Yoseph, Y., Gagne, R., Parvathy, M.R., Mitchell, D.A., and Momoi, T. (1989). Leukocyte and plasma N-laurylsphingosine deacylase (ceramidase) in Farber disease. Clin. Genet. 36, 38–42.10.1111/j.1399-0004.1989.tb03364.xSearch in Google Scholar

Coant, N., Sakamoto, W., Mao, C., and Hannun, Y.A. (2017). Ceramidases, roles in sphingolipid metabolism and in health and disease. Adv. Biol. Regul. 63, 122–131.10.1016/j.jbior.2016.10.002Search in Google Scholar

Dulaney, J.T., Milunsky, A., Sidbury, J.B., Hobolth, N., and Moser, H.W. (1976). Diagnosis of lipogranulomatosis (Farber disease) by use of cultured fibroblasts. J. Pediatr. 89, 59–61.10.1016/S0022-3476(76)80927-4Search in Google Scholar

Dworski, S., Berger, A., Furlonger, C., Moreau, J.M., Yoshimitsu, M., Trentadue, J., Au, B.C., Paige, C.J., and Medin, J.A. (2015). Markedly perturbed hematopoiesis in acid ceramidase deficient mice. Haematologica 100, e162–e165.10.3324/haematol.2014.108530Search in Google Scholar PubMed PubMed Central

Dworski, S., Lu, P., Khan, A., Maranda, B., Mitchell, J.J., Parini, R., Di Rocco, M., Hugle, B., Yoshimitsu, M., Magnusson, B., et al. (2017). Acid ceramidase deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy. Biochim. Biophys. Acta 1863, 386–394.10.1016/j.bbadis.2016.11.031Search in Google Scholar PubMed PubMed Central

Dyment, D.A., Sell, E., Vanstone, M.R., Smith, A.C., Garandeau, D., Garcia, V., Carpentier, S., Le Trionnaire, E., Sabourdy, F., Beaulieu, C.L., et al. (2014). Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy. Clin. Genet. 86, 558–563.10.1111/cge.12307Search in Google Scholar PubMed

Ehlert, K., Roth, J., Frosch, M., Fehse, N., Zander, N., and Vormoor, J. (2006). Farber’s disease without central nervous system involvement: bone-marrow transplantation provides a promising new approach. Ann. Rheum. Dis. 65, 1665–1666.10.1136/ard.2005.048322Search in Google Scholar PubMed PubMed Central

Eliyahu, E., Park, J.H., Shtraizent, N., He, X., and Schuchman, E.H. (2007). Acid ceramidase is a novel factor required for early embryo survival. FASEB J. 21, 1403–1409.10.1096/fj.06-7016comSearch in Google Scholar PubMed

Farber, S., Cohen, J., and Uzman, L.L. (1957). Lipogranulomatosis, a new lipo-glycoprotein storage disease. J. Mt. Sinai Hosp. N. Y. 24, 816–837.Search in Google Scholar

Fensom, A.H., Benson, P.F., Neville, B.R., Moser, H.W., Moser, A.E., and Dulaney, J.T. (1979). Prenatal diagnosis of Farber’s disease. Lancet ii, 990–992.10.1016/S0140-6736(79)92562-5Search in Google Scholar

Filippov, V., Song, M.A., Zhang, K., Vinters, H.V., Tung, S., Kirsch, W.M., Yang, J., and Duerksen-Hughes, P.J. (2012). Increased ceramide in brains with Alzheimer’s and other neurodegenerative diseases. J. Alzheimers Dis. 29, 537–547.10.3233/JAD-2011-111202Search in Google Scholar

Filosto, M., Aureli, M., Castellotti, B., Rinaldi, F., Schiumarini, D., Valsecchi, M., Lualdi, S., Mazzotti, R., Pensato, V., Rota, S., et al. (2016). ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study. Eur. J. Hum. Genet. 24, 1578–1583.10.1038/ejhg.2016.28Search in Google Scholar

Fujiwaki, T., Hamanaka, S., Koga, M., Ishihara, T., Nishikomori, R., Kinoshita, E., and Furusho, K. (1992). A case of Farber disease. Acta Paediatr. Jpn. 34, 72–79.10.1111/j.1442-200X.1992.tb00928.xSearch in Google Scholar

Fujiwaki, T., Hamanaka, S., Tate, S., Inagaki, F., Suzuki, M., Suzuki, A., and Mori, C. (1995). Tissue accumulation of sulfatide and GM3 ganglioside in a patient with variant Farber disease. Clin. Chim. Acta 234, 23–36.10.1016/0009-8981(94)05970-4Search in Google Scholar

Gan, J.J., Garcia, V., Tian, J., Tagliati, M., Parisi, J.E., Chung, J.M., Lewis, R., Baloh, R., Levade, T., and Pierson, T.M. (2015). Acid ceramidase deficiency associated with spinal muscular atrophy with progressive myoclonic epilepsy. Neuromuscul. Disord. 25, 959–963.10.1016/j.nmd.2015.09.007Search in Google Scholar PubMed

Gulbins, E., Palmada, M., Reichel, M., Luth, A., Bohmer, C., Amato, D., Müller, C.P., Tischbirek, C.H., Groemer, T.W., Tabatabai, G., et al. (2013). Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs. Nat. Med. 19, 934–938.10.1038/nm.3214Search in Google Scholar PubMed

He, X., Dworski, S., Zhu, C., DeAngelis, V., Solyom, A., Medin, J.A., Simonaro, C.M., and Schuchman, E.H. (2017). Enzyme replacement therapy for Farber disease: proof-of-concept studies in cells and mice. Biochim. Biophys. Acta Clin. 7, 85–96.10.1016/j.bbacli.2017.02.001Search in Google Scholar PubMed PubMed Central

Huston, J.P., Kornhuber, J., Mühle, C., Japtok, L., Komorowski, M., Mattern, C., Reichel, M., Gulbins, E., Kleuser, B., Topic, B., et al. (2016). A sphingolipid mechanism for behavioral extinction. J. Neurochem. 137, 589–603.10.1111/jnc.13537Search in Google Scholar PubMed

Iqbal, J., Walsh, M.T., Hammad, S.M., and Hussain, M.M. (2017). Sphingolipids and lipoproteins in health and metabolic disorders. Trends Endocrinol. Metab. 28, 506–518.10.1016/j.tem.2017.03.005Search in Google Scholar PubMed PubMed Central

Jones, E.E., Dworski, S., Canals, D., Casas, J., Fabrias, G., Schoenling, D., Levade, T., Denlinger, C., Hannun, Y.A., Medin, J.A., et al. (2014). On-tissue localization of ceramides and other sphingolipids by MALDI mass spectrometry imaging. Anal. Chem. 86, 8303–8311.10.1021/ac501937dSearch in Google Scholar

Kosinska, M.K., Liebisch, G., Lochnit, G., Wilhelm, J., Klein, H., Kaesser, U., Lasczkowski, G., Rickert, M., Schmitz, G., and Steinmeyer, J. (2014). Sphingolipids in human synovial fluid–a lipidomic study. PLoS One 9, e91769.10.1371/journal.pone.0091769Search in Google Scholar

Kostik, M.M., Chikova, I.A., Avramenko, V.V., Vasyakina, L.I., Le Trionnaire, E., Chasnyk, V.G., and Levade, T. (2013). Farber lipogranulomatosis with predominant joint involvement mimicking juvenile idiopathic arthritis. J. Inherit. Metab. Dis. 36, 1079–1080.10.1007/s10545-012-9573-zSearch in Google Scholar

Kudoh, T. and Wenger, D.A. (1982). Diagnosis of metachromatic leukodystrophy, Krabbe disease, and Farber disease after uptake of fatty acid-labeled cerebroside sulfate into cultured skin fibroblasts. J. Clin. Invest. 70, 89–97.10.1172/JCI110607Search in Google Scholar

Levade, T., Tempesta, M.C., and Salvayre, R. (1993). The in situ degradation of ceramide, a potential lipid mediator, is not completely impaired in Farber disease. FEBS Lett. 329, 306–312.10.1016/0014-5793(93)80243-NSearch in Google Scholar

Levade, T., Moser, H.W., Fensom, A.H., Harzer, K., Moser, A.B., and Salvayre, R. (1995). Neurodegenerative course in ceramidase deficiency (Farber disease) correlates with the residual lysosomal ceramide turnover in cultured living patient cells. J. Neurol. Sci. 134, 108–114.10.1016/0022-510X(95)00231-0Search in Google Scholar

Levade, T., Leruth, M., Graber, D., Moisand, A., Vermeersch, S., Salvayre, R., and Courtoy, P.J. (1996). In situ assay of acid sphingomyelinase and ceramidase based on LDL-mediated lysosomal targeting of ceramide-labeled sphingomyelin. J. Lipid Res. 37, 2525–2538.10.1016/S0022-2275(20)37457-5Search in Google Scholar

Li, C.M., Hong, S.B., Kopal, G., He, X., Linke, T., Hou, W.S., Koch, J., Gatt, S., Sandhoff, K., and Schuchman, E.H. (1998). Cloning and characterization of the full-length cDNA and genomic sequences encoding murine acid ceramidase. Genomics 50, 267–274.10.1006/geno.1998.5334Search in Google Scholar PubMed

Li, C.M., Park, J.H., He, X., Levy, B., Chen, F., Arai, K., Adler, D.A., Disteche, C.M., Koch, J., Sandhoff, K., et al. (1999). The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression. Genomics 62, 223–231.10.1006/geno.1999.5940Search in Google Scholar PubMed

Li, C.M., Park, J.H., Simonaro, C.M., He, X., Gordon, R.E., Friedman, A.H., Ehleiter, D., Paris, F., Manova, K., Hepbildikler, S., et al. (2002). Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes. Genomics 79, 218–224.10.1006/geno.2002.6686Search in Google Scholar PubMed

Mondal, R.K., Nandi, M., Datta, S., and Hira, M. (2009). Disseminated lipogranulomatosis. Indian Pediatr. 46, 175–177.Search in Google Scholar

Moser, H.W.L.T., Fensom, A. H., Levade, T., Sandhoff, K. (2001). Acid ceramidase deficiency: Farber lipogranulomatosis. In: The Metabolic and Molecular Bases of Inherited Diseases (New York: McGraw-Hill Inc.), pp. 3573–3588.Search in Google Scholar

Peister, A., Mellad, J.A., Larson, B.L., Hall, B.M., Gibson, L.F., and Prockop, D.J. (2004). Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 103, 1662–1668.10.1182/blood-2003-09-3070Search in Google Scholar

Quillin, R.C., 3rd, Wilson, G.C., Nojima, H., Freeman, C.M., Wang, J., Schuster, R.M., Blanchard, J.A., Edwards, M.J., Gandhi, C.R., Gulbins, E., et al. (2015). Inhibition of acidic sphingomyelinase reduces established hepatic fibrosis in mice. Hepatol. Res. 45, 305–314.10.1111/hepr.12352Search in Google Scholar

Schuchman, E.H. and Desnick, R.J. (2017). Types A and B Niemann-Pick disease. Mol. Genet. Metab. 120, 27–33.10.1016/j.ymgme.2016.12.008Search in Google Scholar

Shtraizent, N., Eliyahu, E., Park, J.H., He, X., Shalgi, R., and Schuchman, E.H. (2008). Autoproteolytic cleavage and activation of human acid ceramidase. J. Biol. Chem. 283, 11253–11259.10.1074/jbc.M709166200Search in Google Scholar

Sikora, J., Dworski, S., Jones, E.E., Kamani, M.A., Micsenyi, M.C., Sawada, T., Le Faouder, P., Bertrand-Michel, J., Dupuy, A., Dunn, C.K., et al. (2017). Acid ceramidase deficiency in mice results in a broad range of central nervous system abnormalities. Am. J. Pathol. 187, 864–883.10.1016/j.ajpath.2016.12.005Search in Google Scholar

Singh, I., Pahan, K., Khan, M., and Singh, A.K. (1998). Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases. J. Biol. Chem. 273, 20354–20362.10.1074/jbc.273.32.20354Search in Google Scholar

Sólyom, A., Karabul, N., Hügle, B., Simonaro, C., and Schuchman, E. (2014). Polyarticular arthritis as presenting feature of Farber disease: a lysosomal storage disease involving inflammation. Pediatr. Rheumatol. 12, P285.10.1186/1546-0096-12-S1-P285Search in Google Scholar

Sugita, M., Dulaney, J.T., and Moser, H.W. (1972). Ceramidase deficiency in Farber’s disease (lipogranulomatosis). Science 178, 1100–1102.10.1126/science.178.4065.1100Search in Google Scholar

Sugita, M., Willians, M., Dulaney, J.T., and Moser, H.W. (1975). Ceramidase and ceramide synthesis in human kidney and cerebellum. Description of a new alkaline ceramidase. Biochim. Biophys. Acta 398, 125–131.10.1016/0005-2760(75)90176-9Search in Google Scholar

Teichgräber, V., Ulrich, M., Endlich, N., Riethmüller, J., Wilker, B., De Oliveira-Munding, C.C., van Heeckeren, A.M., Barr, M.L., von Kürthy, G., et al. (2008). Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat. Med. 14, 382–391.10.1038/nm1748Search in Google Scholar PubMed

Torcoletti, M., Petaccia, A., Pinto, R.M., Hladnik, U., Locatelli, F., Agostoni, C., and Corona, F. (2014). Farber disease in infancy resembling juvenile idiopathic arthritis: identification of two new mutations and a good early response to allogeneic haematopoietic stem cell transplantation. Rheumatology (Oxford) 53, 1533–1534.10.1093/rheumatology/keu010Search in Google Scholar PubMed

Tsuboi, K., Sun, Y.X., Okamoto, Y., Araki, N., Tonai, T., and Ueda, N. (2005). Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J. Biol. Chem. 280, 11082–11092.10.1074/jbc.M413473200Search in Google Scholar PubMed

Vasiliauskaite-Brooks, I., Sounier, R., Rochaix, P., Bellot, G., Fortier, M., Hoh, F., De Colibus, L., Bechara, C., Saied, E.M., Arenz, C., et al. (2017). Structural insights into adiponectin receptors suggest ceramidase activity. Nature 544, 120–123.10.1038/nature21714Search in Google Scholar PubMed PubMed Central

Yeager, A.M., Uhas, K.A., Coles, C.D., Davis, P.C., Krause, W.L., and Moser, H.W. (2000). Bone marrow transplantation for infantile ceramidase deficiency (Farber disease). Bone Marrow Transplant. 26, 357–363.10.1038/sj.bmt.1702489Search in Google Scholar PubMed

Yu, F.P., Islam, D., Sikora, J., Dworski, S., Gurka, J., Lopez-Vasquez, L., Liu, M., Kuebler, W.M., Levade, T., Zhang, H., et al. (2018). Chronic lung injury and impaired pulmonary function in a mouse model of acid ceramidase deficiency. Am. J. Physiol. Lung Cell. Mol. Physiol. 314, L406–L420.10.1152/ajplung.00223.2017Search in Google Scholar PubMed PubMed Central

Zaugg, P., Djonov, V., Fuchtbauer, E.M., and Draeger, A. (1999). Sorting of murine vascular smooth muscle cells during wound healing in the chicken chorioallantoic membrane. Exp. Cell. Res. 253, 599–606.10.1006/excr.1999.4712Search in Google Scholar PubMed

Zhang, Z., Mandal, A.K., Mital, A., Popescu, N., Zimonjic, D., Moser, A., Moser, H., and Mukherjee, A.B. (2000). Human acid ceramidase gene: novel mutations in Farber disease. Mol. Genet. Metab. 70, 301–309.10.1006/mgme.2000.3029Search in Google Scholar PubMed

Zhou, J., Tawk, M., Tiziano, F.D., Veillet, J., Bayes, M., Nolent, F., Garcia, V., Servidei, S., Bertini, E., Castro-Giner, F., et al. (2012). Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. Am. J. Hum. Genet. 91, 5–14.10.1016/j.ajhg.2012.05.001Search in Google Scholar PubMed PubMed Central

Supplementary Material:

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0170).

Received: 2018-02-27
Accepted: 2018-05-07
Published Online: 2018-06-21
Published in Print: 2018-09-25

©2018 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Highlight: sphingolipids in infectious biology and immunology
  3. Sphingolipids in early viral replication and innate immune activation
  4. The function of sphingomyelinases in mycobacterial infections
  5. The role of acid sphingomyelinase and modulation of sphingolipid metabolism in bacterial infection
  6. The neutral sphingomyelinase 2 in T cell receptor signaling and polarity
  7. Click reactions with functional sphingolipids
  8. Sphingolipids in inflammatory hypoxia
  9. CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase
  10. Pathological manifestations of Farber disease in a new mouse model
  11. Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of α-toxin
  12. Minireview
  13. Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding
  14. Research Articles/Short Communications
  15. Proteolysis
  16. The two cathepsin B-like proteases of Arabidopsis thaliana are closely related enzymes with discrete endopeptidase and carboxydipeptidase activities
https://doi.org/10.1515/hsz-2018-0170
Keywords for this article
acid ceramidase; ceramide; Farber disease; lysosomal storage disorders

Articles in the same Issue

  1. Frontmatter
  2. Highlight: sphingolipids in infectious biology and immunology
  3. Sphingolipids in early viral replication and innate immune activation
  4. The function of sphingomyelinases in mycobacterial infections
  5. The role of acid sphingomyelinase and modulation of sphingolipid metabolism in bacterial infection
  6. The neutral sphingomyelinase 2 in T cell receptor signaling and polarity
  7. Click reactions with functional sphingolipids
  8. Sphingolipids in inflammatory hypoxia
  9. CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase
  10. Pathological manifestations of Farber disease in a new mouse model
  11. Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of α-toxin
  12. Minireview
  13. Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding
  14. Research Articles/Short Communications
  15. Proteolysis
  16. The two cathepsin B-like proteases of Arabidopsis thaliana are closely related enzymes with discrete endopeptidase and carboxydipeptidase activities
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