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Lowering effect of dimethyl-α-cyclodextrin on GM1-ganglioside accumulation in GM1-gangliosidosis model cells and in brain of β-galactosidase-knockout mice

  • Yuki Maeda
  • Keiichi Motoyama
  • Taishi Higashi
  • Risako Onodera
  • Toru Takeo
  • Naomi Nakagata
  • Yuki Kurauchi
  • Hiroshi Katsuki
  • Yoichi Ishitsuka
  • Yuki Kondo
  • Tetsumi Irie
  • Takumi Era
  • Hidetoshi ArimaEmail author
Original Article
  • 65 Downloads

Abstract

GM1-gangliosidosis (GM1G) is caused by a deficiency of β-galactosidase, resulting in the excessive accumulation of GM1-ganglioside (GM1) in lysosomes of cells, particularly in the nerve cells (neurons). There is no treatment available for patients with GM1G. Meanwhile, cyclodextrins (CyDs) are cyclic oligosaccharides, which are widely used in the pharmaceutical field. We previously reported that 2, 6-di-O-methyl-α-CyD (DM-α-CyD) extracted phospholipids from lipid rafts, which are abundant with sphingolipids including GM1. Therefore, in the present study, we investigated the effects of α-CyDs on GM1 levels in GM1G model cells and in brain of GM1G model mice. The interaction of DM-α-CyD with GM1 was stronger than that of 2-hydroxypropyl-α-CyD. Additionally, DM-α-CyD significantly reduced GM1 levels in GM1G model cells at 1 mM for 24 h. Furthermore, DM-α-CyD decreased GM1 levels in brain after an intraventricular administration to GM1G model mice without any significant side effects. These results strongly suggest that DM-α-CyD decreased the accumulation of GM1 in not only GM1G model cells but also GM1G model mice. Collectively, DM-α-CyD may have the potential as a therapeutic drug for GM1G.

Keywords

Cyclodextrins GM1-gangliosidosis GM1-ganglioside, cholesterol, lysosomes 

Notes

Acknowledgements

This work was supported by Grant-in-Aid for JSPS Research Fellow (16J11970) and Health and Labor Sciences Research Grant in Japan (17bk01040015h0005).

Compliance with ethical standards

Conflict of interest

There is no conflict of interest in this paper.

Supplementary material

10847_2018_835_MOESM1_ESM.pptx (65 kb)
Supplementary Figure S1 TUNEL analysis of brain after intraventricular injection of DM-α-CyD to WT mice. Twenty four h after intraventricular injection of 1 μL of solution containing 431.6 mM DM-α-CyD to WT mice, the brain was collected and 7 μm sequential coronal sections were prepared. TUNEL assay was performed by using the Apoptosis in Situ Detection Kit. The images were representative data of 3 experiments. (PPTX 65 KB)

References

  1. 1.
    Vellodi, A.: Lysosomal storage disorders. Br. J. Haematol. 128, 413–431 (2005)Google Scholar
  2. 2.
    Winchester, B., Vellodi, A., Young, E.: The molecular basis of lysosomal storage diseases and their treatment. Biochem. Soc. Trans. 28, 150–154 (2000)Google Scholar
  3. 3.
    Brunetti-Pierri, N., Scaglia, F.: GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol. Genet. Metab. 94, 391–396 (2008)Google Scholar
  4. 4.
    Front, S., Biela-Banas, A., Burda, P., Ballhausen, D., Higaki, K., Caciotti, A., Morrone, A., Charollais-Thoenig, J., Gallienne, E., Demotz, S., Martin, O.R.: (5aR)-5a-C-Pentyl-4-epi-isofagomine: a powerful inhibitor of lysosomal beta-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B. Eur. J. Med. Chem. 126, 160–170 (2017)Google Scholar
  5. 5.
    Takai, T., Higaki, K., Aguilar-Moncayo, M., Mena-Barragan, T., Hirano, Y., Yura, K., Yu, L., Ninomiya, H., Garcia-Moreno, M.I., Sakakibara, Y., Ohno, K., Nanba, E., Ortiz Mellet, O., Garcia Fernandez, J.M., Suzuki, Y.: A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis. Mol. Ther. 21, 526–532 (2013)Google Scholar
  6. 6.
    Tapmura, A., Higaki, K., Ninomiya, H., Takai, T., Matsuda, J., Iida, M., Ohno, K., Suzuki, Y., Nanba, E.: Lysosomal accumulation of Trk protein in brain of GM1-gangliosidosis mouse and its restoration by chemical chaperone. J. Neurochem. 118, 399–406 (2011)Google Scholar
  7. 7.
    Suzuki, Y., Ichinomiya, S., Kurosawa, M., Ohkubo, M., Watanabe, H., Iwasaki, H., Matsuda, J., Noguchi, Y., Takimoto, K., Itoh, M., Tabe, M., Iida, M., Kubo, T., Ogawa, S., Nanba, E., Higaki, K., Ohno, K., Brady, R.O.: Chemical chaperone therapy: clinical effect in murine GM1-gangliosidosis. Ann. Neurol. 62, 671–675 (2007)Google Scholar
  8. 8.
    Condori, J., Acosta, W., Ayala, J., Katta, V., Flory, A., Martin, R., Radin, J., Cramer, C.L., Radin, D.N.: Enzyme replacement for GM1-gangliosidosis: uptake, LYSOSOMAL activation, and cellular disease correction using a novel β-galactosidase: RTB lectin fusion. Mol. Genet. Metab. 117, 199–209 (2016)Google Scholar
  9. 9.
    Samoylova, T.I., Martin, D.R., Morrison, N.E., Hwang, M., Cochran, A.M., Samoylov, A.M., Baker, H.J., Cox, N.R.: Generation and characterization of recombinant feline β-galactosidase for preclinical enzyme replacement therapy studies in GM1 gangliosidosis. Metab. Brain Dis. 23, 161–173 (2008)Google Scholar
  10. 10.
    Hayward, C., Patel, H.C., Manohar, S.G., Lyon, A.R.: Gene therapy for GM1 gangliosidosis: challenges of translational medicine. Ann. Transl. Med. 3, S28 (2015)Google Scholar
  11. 11.
    Weismann, C.M., Ferreira, J., Keeler, A.M., Su, Q., Qui, L., Shaffer, S.A., Xu, Z., Gao, G., Sena-Esteves, M.: Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan. Hum. Mol. Genet. 24, 4353–4364 (2015)Google Scholar
  12. 12.
    Baek, R.C., Broekman, M.L., Leroy, S.G., Tierney, L.A., Sandberg, M.A., d’Azzo, A., Seyfried, T.N., Sena-Esteves, M.: AAV-mediated gene delivery in adult GM1-gangliosidosis mice corrects lysosomal storage in CNS and improves survival. PloS ONE 5, e13468 (2010)Google Scholar
  13. 13.
    Loftsson, T., Brewster, M.E.: Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J. Pharm. Sci. 85, 1017–1025 (1996)Google Scholar
  14. 14.
    Rajewski, R.A., Stella, V.J.: Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery. J. Pharm. Sci. 85, 1142–1169 (1996)Google Scholar
  15. 15.
    Uekama, K.: Design and evaluation of cyclodextrin-based drug formulation. Chem. Pharm. Bull. 52, 900–915 (2004)Google Scholar
  16. 16.
    Uekama, K., Hirayama, F., Irie, T.: Cyclodextrin drug carrier systems. Chem. Rev. 98, 2045–2076 (1998)Google Scholar
  17. 17.
    Motoyama, K., Toyodome, H., Onodera, R., Irie, T., Hirayama, F., Uekama, K., Arima, H.: Involvement of lipid rafts of rabbit red blood cells in morphological changes induced by methylated β-cyclodextrins. Biol Pharm Bull 32, 700–705 (2009)Google Scholar
  18. 18.
    Motoyama, K., Arima, H., Toyodome, H., Irie, T., Hirayama, F., Uekama, K.: Effect of 2,6-di-O-methyl-α-cyclodextrin on hemolysis and morphological change in rabbit’s red blood cells. Eur. J. Pharm. Sci. 29, 111–119 (2006)Google Scholar
  19. 19.
    Darblade, B., Caillaud, D., Poirot, M., Fouque, M., Thiers, J.C., Rami, J., Bayard, F., Arnal, J.F.: Alteration of plasmalemmal caveolae mimics endothelial dysfunction observed in atheromatous rabbit aorta. Cardiovasc. Res. 50, 566–576 (2001)Google Scholar
  20. 20.
    Parpal, S., Karlsson, M., Thorn, H., Stralfors, P.: Cholesterol depletion disrupts caveolae and insulin receptor signaling for metabolic control via insulin receptor substrate-1, but not for mitogen-activated protein kinase control. J. Biol. Chem. 276, 9670–9678 (2001)Google Scholar
  21. 21.
    Tanaka, Y., Yamada, Y., Ishitsuka, Y., Matsuo, M., Shiraishi, K., Wada, K., Uchio, Y., Kondo, Y., Takeo, T., Nakagata, N., Higashi, T., Motoyama, K., Arima, H., Mochinaga, S., Higaki, K., Ohno, K., Irie, T.: Efficacy of 2-hydroxypropyl-β-cyclodextrin in Niemann-Pick disease type C model mice and its pharmacokinetic analysis in a patient with the disease. Biol. Pharm. Bull. 38, 844–851 (2015)Google Scholar
  22. 22.
    Liu, B., Turley, S.D., Burns, D.K., Miller, A.M., Repa, J.J., Dietschy, J.M.: Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1 –/– mouse. Proc. Natl. Acad. Sci. USA 106, 2377–2382 (2009)Google Scholar
  23. 23.
    Camargo, F., Erickson, R.P., Garver, W.S., Hossain, G.S., Carbone, P.N., Heidenreich, R.A., Blanchard, J.: Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease. Life Sci. 70, 131–142 (2001)Google Scholar
  24. 24.
    Maeda, Y., Motoyama, K., Higashi, T., Horikoshi, Y., Takeo, T., Nakagata, N., Kurauchi, Y., Katsuki, H., Ishitsuka, Y., Kondo, Y., Irie, T., Furuya, H., Era, T., Arima, H.: Effects of cyclodextrins on GM1-gangliosides in fibroblasts from GM1-gangliosidosis patients. J. Pharm. Pharmacol. 67, 1133–1142 (2015)Google Scholar
  25. 25.
    Yan, Y., Shin, S., Jha, B.S., Liu, Q., Sheng, J., Li, F., Zhan, M., Davis, J., Bharti, K., Zeng, X., Rao, M., Malik, N., Vemuri, M.C.: Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells. Stem Cells Transl. Med. 2, 862–870 (2013)Google Scholar
  26. 26.
    Matsuda, J., Suzuki, O., Oshima, A., Ogura, A., Noguchi, Y., Yamamoto, Y., Asano, T., Takimoto, K., Sukegawa, K., Suzuki, Y., Naiki, M.: β-Galactosidase-deficient mouse as an animal model for GM1-gangliosidosis. Glycoconj. J. 14, 729–736 (1997)Google Scholar
  27. 27.
    Nabi, I.R., Le, P.U.: Caveolae/raft-dependent endocytosis. J. Cell Biol. 161, 673–677 (2003)Google Scholar
  28. 28.
    Connors, K.A.: The stability of cyclodextrin complexes in solution. Chem. Rev. 97, 1325–1358 (1997)Google Scholar
  29. 29.
    Neufeld, E.B., Wastney, M., Patel, S., Suresh, S., Cooney, A.M., Dwyer, N.K., Roff, C.F., Ohno, K., Morris, J.A., Carstea, E.D., Incardona, J.P., Strauss, J.F. 3rd, Vanier, M.T., Patterson, M.C., Brady, R.O., Pentchev, P.G., Blanchette-Mackie, E.J.: The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. J. Biol. Chem. 274, 9627–9635 (1999)Google Scholar
  30. 30.
    Higgins, M.E., Davies, J.P., Chen, F.W., Ioannou, Y.A.: Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol. Genet. Metab. 68, 1–13 (1999)Google Scholar
  31. 31.
    Fantur, K., Hofer, D., Schitter, G., Steiner, A.J., Pabst, B.M., Wrodnigg, T.M., Stutz, A.E., Paschke, E.: DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human GM1-gangliosidosis fibroblasts. Mol. Genet. Metab. 100, 262–268 (2010)Google Scholar
  32. 32.
    Rosenbaum, A.I., Zhang, G., Warren, J.D., Maxfield, F.R.: Endocytosis of β-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells. Proc. Natl. Acad. Sci. USA 107, 5477–5482 (2010)Google Scholar
  33. 33.
    Takamura, A., Higaki, K., Kajimaki, K., Otsuka, S., Ninomiya, H., Matsuda, J., Ohno, K., Suzuki, Y., Nanba, E.: Enhanced autophagy and mitochondrial aberrations in murine GM1-gangliosidosis. Biochem. Biophys. Res. Commun. 367, 616–622 (2008)Google Scholar
  34. 34.
    Sano, R., Annunziata, I., Patterson, A., Moshiach, S., Gomero, E., Opferman, J., Forte, M., d’Azzo, A.: GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca2+-dependent mitochondrial apoptosis. Mol. Cell 36, 500–511 (2009)Google Scholar
  35. 35.
    Ottinger, E.A., Kao, M.L., Carrillo-Carrasco, N., Yanjanin, N., Shankar, R.K., Janssen, M., Brewster, M., Scott, I., Xu, X., Cradock, J., Terse, P., Dehdashti, S.J., Marugan, J., Zheng, W., Portilla, L., Hubbs, A., Pavan, W.J., Heiss, J., Vite, C.H., Walkley, S.U., Ory, D.S., Silber, S.A., Porter, F.D., Austin, C.P., McKew, J.C.: Collaborative development of 2-hydroxypropyl-β-cyclodextrin for the treatment of Niemann-Pick type C1 disease. Curr. Top. Med. Chem. 14, 330–339 (2014)Google Scholar
  36. 36.
    Aqul, A., Liu, B., Ramirez, C.M., Pieper, A.A., Estill, S.J., Burns, D.K., Liu, B., Repa, J.J., Turley, S.D., Dietschy, J.M.: Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment. J. Neurosci. 31, 9404–9413 (2011)Google Scholar
  37. 37.
    Davidson, C.D., Ali, N.F., Micsenyi, M.C., Stephney, G., Renault, S., Dobrenis, K., Ory, D.S., Vanier, M.T., Walkley, S.U.: Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PloS ONE 4, e6951 (2009)Google Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Yuki Maeda
    • 1
    • 2
  • Keiichi Motoyama
    • 1
  • Taishi Higashi
    • 1
  • Risako Onodera
    • 1
  • Toru Takeo
    • 3
  • Naomi Nakagata
    • 3
  • Yuki Kurauchi
    • 1
  • Hiroshi Katsuki
    • 1
  • Yoichi Ishitsuka
    • 1
  • Yuki Kondo
    • 1
  • Tetsumi Irie
    • 1
    • 2
  • Takumi Era
    • 4
  • Hidetoshi Arima
    • 1
    • 2
    Email author
  1. 1.Graduate School of Pharmaceutical SciencesKumamoto UniversityKumamotoJapan
  2. 2.Program for Leading Graduate Schools “HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program”Kumamoto UniversityKumamotoJapan
  3. 3.Center for Animal Resources and DevelopmentKumamoto UniversityKumamotoJapan
  4. 4.Department of Cell Modulation, Institute of Molecular Embryology and GeneticsKumamoto UniversityKumamotoJapan

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