Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain

1. Mencarelli C, Martinez-Martinez P (2013) Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 70: 181–203. doi: 10.1007/s00018-012-1038-x 22729185

2. Buccoliero R, Futerman AH (2003) The roles of ceramide and complex sphingolipids in neuronal cell function. Pharmacol Res 47: 409–419. 12676515

3. Meng H, Yuan Y, Lee VM (2011) Loss of Sphingosine Kinase 1/S1P Signaling Impairs Cell Growth and Survival of Neurons and Progenitor Cells in the Developing Sensory Ganglia. Plos One 6.

4. Lee H, Lee JK, Min WK, Bae JH, He XH, et al. (2010) Bone Marrow-Derived Mesenchymal Stem Cells Prevent the Loss of Niemann-Pick Type C Mouse Purkinje Neurons by Correcting Sphingolipid Metabolism and Increasing Sphingosine-1-phosphate. Stem Cells 28: 821–831. doi: 10.1002/stem.401 20201063

5. Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, et al. (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci U S A 101: 2070–2075. 14970312

6. Ben-David O, Futerman AH (2010) The Role of the Ceramide Acyl Chain Length in Neurodegeneration: Involvement of Ceramide Synthases. Neuromol Med 12: 341–350.

7. Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed Cell-Death Induced by Ceramide. Science 259: 1769–1771. 8456305

8. Venable ME, Lee JY, Smyth MJ, Bielawska A, Obeid LM (1995) Role of ceramide in cellular senescence. J Biol Chem 270: 30701–30708. 8530509

9. Mullen TD, Hannun YA, Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J 441: 789–802. doi: 10.1042/BJ20111626 22248339

10. Ternes P, Franke S, Zahringer U, Sperling P, Heinz E (2002) Identification and characterization of a sphingolipid Delta 4-desaturase family. J Biol Chem 277: 25512–25518. 11937514

11. Mizutani Y, Kihara A, Igarashi Y (2004) Identification of the human sphingolipid C4-hydroxylase, hDES2, and its up-regulation during keratinocyte differentiation. Febs Lett 563: 93–97. 15063729

12. Jiang JC, Kirchman PA, Zagulski M, Hunt J, Jazwinski SM (1998) Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human. Genome Res 8: 1259–1272. 9872981

13. Laviad EL, Albee L, Pankova-Kholmyansky I, Epstein S, Park H, et al. (2008) Characterization of ceramide synthase 2—Tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J Biol Chem 283: 5677–5684. doi: 10.1074/jbc.M707386200 18165233

14. Mizutani Y, Kihara A, Igarashi Y (2006) LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity. Biochem J 398: 531–538. 16753040

15. Lahiri S, Futerman AH (2005) LASS5 is a bona fide dihydroceramide synthase that selectively utilizes palmitoyl-CoA as acyl donor. J Biol Chem 280: 33735–33738. 16100120

16. Riebeling C, Allegood JC, Wang E, Merrill AH, Futerman AH (2003) Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors. J Biol Chem 278: 43452–43459. 12912983

17. Mizutani Y, Kihara A, Igarashi Y (2005) Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 390: 263–271. 15823095

18. Gillard BK, Clement RG, Marcus DM (1998) Variations among cell lines in the synthesis of sphingolipids in de novo and recycling pathways. Glycobiology 8: 885–890. 9675221

19. Kitatani K, Idkowiak-Baldys J, Hannun YA (2008) The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 20: 1010–1018. doi: 10.1016/j.cellsig.2007.12.006 18191382

20. Mandon EC, Ehses I, Rother J, Vanechten G, Sandhoff K (1992) Subcellular-Localization and Membrane Topology of Serine Palmitoyltransferase, 3-Dehydrosphinganine Reductase, and Sphinganine N-Acyltransferase in Mouse-Liver. J Biol Chem 267: 11144–11148. 1317856

21. Hirschberg K, Rodger J, Futerman AH (1993) The Long-Chain Sphingoid Base of Sphingolipids Is Acylated at the Cytosolic Surface of the Endoplasmic-Reticulum in Rat-Liver. Biochem J 290: 751–757. 8457204

22. Funato K, Riezman H (2001) Vesicular and nonvesicular transport of ceramide from ER to the Golgi apparatus in yeast. J Cell Biol 155: 949–959. 11733544

23. Perry RJ, Ridgway ND (2005) Molecular mechanisms and regulation of ceramide transport. Bba-Mol Cell Biol L 1734: 220–234.

24. Liu B, Hassler DF, Smith GK, Weaver K, Hannun YA (1998) Purification and characterization of a membrane bound neutral pH optimum magnesium-dependent and phosphatidylserine-stimulated sphingomyelinase from rat brain. J Biol Chem 273: 34472–34479. 9852115

25. Quintern LE, Schuchman EH, Levran O, Suchi M, Ferlinz K, et al. (1989) Isolation of Cdna Clones Encoding Human Acid Sphingomyelinase—Occurrence of Alternatively Processed Transcripts. Embo J 8: 2469–2473. 2555181

26. Koch J, Gartner S, Li CM, Quintern LE, Bernardo K, et al. (1996) Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase—Identification of the first molecular lesion causing Farber disease. J Biol Chem 271: 33110–33115. 8955159

27. El Bawab S, Roddy P, Qian T, Bielawska A, Lemasters JJ, et al. (2000) Molecular cloning and characterization of a human mitochondrial ceramidase. J Biol Chem 275: 21508–21513. 10781606

28. Sun W, Xu RJ, Hu W, Jin JF, Crellin HA, et al. (2008) Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes. J Invest Dermatol 128: 389–397. 17713573

29. Xu RJ, Jin JF, Hu W, Sun W, Bielawski J, et al. (2006) Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P. Faseb J 20: 1813–1825. 16940153

30. Mao CG, Xu RJ, Szulc ZM, Bielawska A, Galadari SH, et al. (2001) Cloning and characterization of a novel human alkaline ceramidase—A mammalian enzyme that hydrolyzes phytoceramide. J Biol Chem 276: 26577–26588. 11356846

31. Mao CG, Obeid LM (2008) Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Bba-Mol Cell Biol L 1781: 424–434.

32. Momoi T, Benyoseph Y, Nadler HL (1982) Substrate-Specificities of Acid and Alkaline Ceramidases in Fibroblasts from Patients with Farber Disease and Controls. Biochem J 205: 419–425. 6814427

33. Tani M, Iida H, Ito M (2003) O-glycosylation of mucin-like domain retains the neutral ceramidase on the plasma membranes as a type II integral membrane protein. J Biol Chem 278: 10523–10530. 12499379

34. El Bawab S, Bielawska A, Hannun YA (1999) Purification and characterization of a membrane-bound nonlysosomal ceramidase from rat brain. J Biol Chem 274: 27948–27955. 10488143

35. Sun W, Jin JF, Xu RJ, Hu W, Szulc ZM, et al. (2010) Substrate Specificity, Membrane Topology, and Activity Regulation of Human Alkaline Ceramidase 2 (ACER2). J Biol Chem 285: 8995–9007. doi: 10.1074/jbc.M109.069203 20089856

36. Hu W, Xu RJ, Sun W, Szulc ZM, Bielawski J, et al. (2010) Alkaline Ceramidase 3 (ACER3) Hydrolyzes Unsaturated Long-chain Ceramides, and Its Down-regulation Inhibits Both Cell Proliferation and Apoptosis. J Biol Chem 285: 7964–7976. doi: 10.1074/jbc.M109.063586 20068046

37. Kono M, Dreier JL, Ellis JM, Allende ML, Kalkofen DN, et al. (2006) Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids. J Biol Chem 281: 7324–7331. 16380386

38. Cheng JC, Bai AP, Beckham TH, Marrison ST, Yount CL, et al. (2013) Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse. J Clin Invest 123: 4344–4358. doi: 10.1172/JCI64791 24091326

39. Beckham TH, Cheng JC, Lu P, Marrison ST, Norris JS, et al. (2013) Acid Ceramidase Promotes Nuclear Export of PTEN through Sphingosine 1-Phosphate Mediated Akt Signaling. Plos One 8.

40. Sugita M, Dulaney JT, Moser HW (1972) Ceramidase deficiency in Farber's disease (lipogranulomatosis). Science 178: 1100–1102. 4678225

41. Alayoubi AM, Wang JCM, Au BCY, Carpentier S, Garcia V, et al. (2013) Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Mol Med 5: 827–842. doi: 10.1002/emmm.201202301 23681708

42. Sacket SJ, Chung HY, Okajima F, Im DS (2009) Increase in sphingolipid catabolic enzyme activity during aging. Acta Pharmacol Sin 30: 1454–1461. doi: 10.1038/aps.2009.136 19749786

43. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Bio 9: 139–150.

44. Thach WT, Goodkin HP, Keating JG (1992) The Cerebellum and the Adaptive Coordination of Movement. Annu Rev Neurosci 15: 403–442. 1575449

45. Zhang CZ, Zhu QF, Hua TM (2010) Aging of cerebellar Purkinje cells. Cell Tissue Res 341: 341–347. doi: 10.1007/s00441-010-1016-2 20652318

46. Jurk D, Wang CF, Miwa S, Maddick M, Korolchuk V, et al. (2012) Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11: 996–1004. doi: 10.1111/j.1474-9726.2012.00870.x 22882466

47. Woodcock J (2006) Sphingosine and ceramide signalling in apoptosis. IUBMB life 58: 462–466. 16916783

48. Ginkel C, Hartmann D, vom Dorp K, Zlomuzica A, Farwanah H, et al. (2012) Ablation of Neuronal Ceramide Synthase 1 in Mice Decreases Ganglioside Levels and Expression of Myelin-associated Glycoprotein in Oligodendrocytes. J Biol Chem 287: 41888–41902. doi: 10.1074/jbc.M112.413500 23074226

49. Imgrund S, Hartmann D, Farwanah H, Eckhardt M, Sandhoff R, et al. (2009) Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem 284: 33549–33560. doi: 10.1074/jbc.M109.031971 19801672

50. He XX, Huang Y, Li B, Gong CX, Schuchman EH (2010) Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol Aging 31: 398–408. doi: 10.1016/j.neurobiolaging.2008.05.010 18547682

51. Matsuda J, Kido M, Tadano-Aritomi K, Ishizuka I, Tominaga K, et al. (2004) Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in mouse. Hum Mol Genet 13: 2709–2723. 15345707

52. Ceccom J, Loukh N, Lauwers-Cances V, Touriol C, Nicaise Y, et al. (2014) Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease. Acta Neuropathol Commun 2: 12. doi: 10.1186/2051-5960-2-12 24468113

53. Lightle SA, Oakley JI, Nikolova-Karakashian MN (2000) Activation of sphingolipid turnover and chronic generation of ceramide and sphingosine in liver during aging. Mech Ageing Dev 120: 111–125. 11087909

54. Rivas DA, Morris EP, Haran PH, Pasha EP, Morais Mda S, et al. (2012) Increased ceramide content and NFkappaB signaling may contribute to the attenuation of anabolic signaling after resistance exercise in aged males. J Appl Physiol 113: 1727–1736. doi: 10.1152/japplphysiol.00412.2012 23042913

55. Ohanian J, Liao A, Forman SP, Ohanian V (2014) Age-related remodeling of small arteries is accompanied by increased sphingomyelinase activity and accumulation of long-chain ceramides. Physiol Rep 2.

56. Levy M, Futerman AH (2010) Mammalian ceramide synthases. IUBMB life 62: 347–356. doi: 10.1002/iub.319 20222015

57. Grosch S, Schiffmann S, Geisslinger G (2012) Chain length-specific properties of ceramides. Prog Lipid Res 51: 50–62. doi: 10.1016/j.plipres.2011.11.001 22133871

58. Zhang H, Desai NN, Olivera A, Seki T, Brooker G, et al. (1991) Sphingosine-1-Phosphate, a Novel Lipid, Involved in Cellular Proliferation. J Cell Biol 114: 155–167. 2050740

59. Zhao L, Spassieva SD, Jucius TJ, Shultz LD, Shick HE, et al. (2011) A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation. PLoS genetics 7: e1002063. doi: 10.1371/journal.pgen.1002063 21625621

60. Darios F, Wasser C, Shakirzyanova A, Giniatullin A, Goodman K, et al. (2009) Sphingosine Facilitates SNARE Complex Assembly and Activates Synaptic Vesicle Exocytosis. Neuron 62: 683–694. doi: 10.1016/j.neuron.2009.04.024 19524527

61. Sun Y, Liou B, Ran HM, Skelton MR, Williams MT, et al. (2010) Neuronopathic Gaucher disease in the mouse: viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits. Hum Mol Genet 19: 1088–1097. doi: 10.1093/hmg/ddp580 20047948

62. Ledesma MD, Prinetti A, Sonnino S, Schuchman EH (2011) Brain pathology in Niemann Pick disease type A: insights from the acid sphingomyelinase knockout mice. J Neurochem 116: 779–788. doi: 10.1111/j.1471-4159.2010.07034.x 21214563

63. Li CM, Park JH, Simonaro CM, He X, Gordon RE, 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. 11829492

64. Eliyahu E, Shtraizent N, Shalgi R, Schuchman EH (2012) Construction of conditional acid ceramidase knockout mice and in vivo effects on oocyte development and fertility. Cell Physiol Biochem 30: 735–748. doi: 10.1159/000341453 22854249

65. Spyropoulos DD, Capecchi MR (1994) Targeted Disruption of the Even-Skipped Gene, Evx1, Causes Early Postimplantation Lethality of the Mouse Conceptus. Gene Dev 8: 1949–1961. 7958869

66. Truett GE, Heeger P, Mynatt RL, Truett AA, Walker JA, et al. (2000) Preparation of PCR-quality mouse genomic DNA with hot sodium hydroxide and tris (HotSHOT). BioTechniques 29: 52, 54. 10907076

67. Mao C, Xu R, Szulc ZM, Bielawski J, Becker KP, et al. (2003) Cloning and characterization of a mouse endoplasmic reticulum alkaline ceramidase: an enzyme that preferentially regulates metabolism of very long chain ceramides. J Biol Chem 278: 31184–31191. 12783875

68. Choi WG, Roberts DM (2007) Arabidopsis NIP2;1, a major intrinsic protein transporter of lactic acid induced by anoxic stress. J Biol Chem 282: 24209–24218. 17584741

69. Kim YS, Harry GJ, Kang HS, Goulding D, Wine RN, et al. (2010) Altered cerebellar development in nuclear receptor TAK1/ TR4 null mice is associated with deficits in GLAST(+) glia, alterations in social behavior, motor learning, startle reactivity, and microglia. Cerebellum 9: 310–323. doi: 10.1007/s12311-010-0163-z 20393820

70. Dere E, De Souza-Silva MA, Frisch C, Teubner B, Sohl G, et al. (2003) Connexin30-deficient mice show increased emotionality and decreased rearing activity in the open-field along with neurochemical changes. Eur J Nerosci 18: 629–638.

71. Carlson CG, Rutter J, Bledsoe C, Singh R, Hoff H, et al. (2010) A simple protocol for assessing inter-trial and inter-examiner reliability for two noninvasive measures of limb muscle strength. J Neurosci Methods 186: 226–230. doi: 10.1016/j.jneumeth.2009.11.006 19917311

72. Dadush O, Aga-Mizrachi S, Ettinger K, Tabakman R, Elbaz M, et al. (2010) Improved muscle strength and mobility in the dy(2J)/dy(2J) mouse with merosin deficient congenital muscular dystrophy treated with Glatiramer acetate. Neuromuscul Disord 20: 267–272. doi: 10.1016/j.nmd.2010.02.002 20304648

73. Tanase K, Teng Q, Krishnaney AA, Liu JK, Garrity-Moses ME, et al. (2004) Cervical spinal cord delivery of a rabies G protein pseudotyped lentiviral vector in the SOD-1 transgenic mouse. Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2004. J Neurosurg Spine 1: 128–136. 15291033

74. Vogel RW, Ewers M, Ross C, Gould TJ, Woodruff-Pak DS (2002) Age-related impairment in the 250-millisecond delay eyeblink classical conditioning procedure in C57BL/6 mice. Learn Mem 9: 321–336. 12359840

75. Graber TG, Ferguson-Stegall L, Kim JH, Thompson LV (2013) C57BL/6 neuromuscular healthspan scoring system. J Gerontol A Biol Sci Med Sci 68: 1326–1336. doi: 10.1093/gerona/glt032 23585418

76. Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, et al. (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J Neurosci 19: 3248–3257. 10191337

77. Guyenet SJ, Furrer SA, Damian VM, Baughan TD, La Spada AR, et al. (2010) A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J Vis Exp

78. Siskova Z, Page A, O'Connor V, Perry VH (2009) Degenerating synaptic boutons in prion disease: microglia activation without synaptic stripping. Am J Pathol 175: 1610–1621. doi: 10.2353/ajpath.2009.090372 19779137

79. Pfeifer CR, Shomorony A, Aronova MA, Zhang G, Cai T, et al. (2015) Quantitative analysis of mouse pancreatic islet architecture by serial block-face SEM. J Struct Biol 189: 44–52. doi: 10.1016/j.jsb.2014.10.013 25448885

80. Walton J (1979) Lead asparate, an en bloc contrast stain particularly useful for ultrastructural enzymology. J Histochem Cytochem 27: 1337–1342. 512319