Molecular Neurobiology

, Volume 56, Issue 7, pp 4760–4777 | Cite as

Ceramide Induces the Death of Retina Photoreceptors Through Activation of Parthanatos

  • Facundo H. Prado Spalm
  • Marcela S. Vera
  • Marcos J. Dibo
  • M. Victoria Simón
  • Luis E. Politi
  • Nora P. RotsteinEmail author


Ceramide (Cer) has a key role inducing cell death and has been proposed as a messenger in photoreceptor cell death in the retina. Here, we explored the pathways induced by C2-acetylsphingosine (C2-Cer), a cell-permeable Cer, to elicit photoreceptor death. Treating pure retina neuronal cultures with 10 μM C2-Cer for 6 h selectively induced photoreceptor death, decreasing mitochondrial membrane potential and increasing the formation of reactive oxygen species (ROS). In contrast, amacrine neurons preserved their viability. Noteworthy, the amount of TUNEL-labeled cells and photoreceptors expressing cleaved caspase-3 remained constant and pretreatment with a pan-caspase inhibitor did not prevent C2-Cer-induced death. C2-Cer provoked polyADP ribosyl polymerase-1 (PARP-1) overactivation. Inhibiting PARP-1 decreased C2-Cer-induced photoreceptor death; C2-Cer increased polyADP ribose polymer (PAR) levels and induced the translocation of apoptosis inducing factor (AIF) from mitochondria to photoreceptor nuclei, which was prevented by PARP-1 inhibition. Pretreatment with a calpain and cathepsin inhibitor and with a calpain inhibitor reduced photoreceptor death, whereas selective cathepsin inhibitors granted no protection. Combined pretreatment with a PARP-1 and a calpain inhibitor evidenced the same protection as each inhibitor by itself. Neither autophagy nor necroptosis was involved in C2-Cer-elicited death; no increase in LDH release was observed upon C2-Cer treatment and pretreatment with inhibitors of necroptosis and autophagy did not rescue photoreceptors. These results suggest that C2-Cer induced photoreceptor death by a novel, caspase-independent mechanism, involving activation of PARP-1, decline of mitochondrial membrane potential, calpain activation, and AIF translocation, all of which are biochemical features of parthanatos.


Photoreceptor death PARP Ceramide AIF Calpain Parthanatos 



N. P. Rotstein and L.E. Politi are principal researchers from the National Research Council of Argentina (CONICET) and Professors of Biological Chemistry and Cell Biology, respectively, from the Universidad Nacional del Sur (UNS). F.H. Prado Spalm, M.S. Vera, and M.J. Dibo are Doctoral Research fellows and M.V. Simon is an Assistant Researcher from CONICET. Funds are from the National Agency for Science and Technology (ANPCYT) (PICT-2015-0284 to NPR); National Research Council of Argentina (CONICET) (PIP 11220-1101–00827, to LEP and NPR); and the Secretary of Science and Technology, Universidad Nacional del Sur (to NPR).

The authors are grateful to E. Beatriz de los Santos and Edgardo Buzzi for their expert technical assistance.

Authors’ Contribution

Facundo Prado Spalm is responsible for planning, conducting, evaluating, and interpreting the experiments and manuscript writing. Marcela Vera is responsible for conducting and evaluating the experiments and manuscript revision. M. Victoria Simón is responsible for conducting and evaluating the experiments and manuscript revision. Luis Politi is responsible for evaluating and interpreting the experiments and manuscript revision. Nora Rotstein is responsible for planning, evaluating, and interpreting the experiments and manuscript writing.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1402_Fig10_ESM.png (305 kb)
Supplementary Fig. 1

Inhibition of cathepsins did not rescue photoreceptors from C2-Cer-elicited death. Cultures were pre-treated or not with different concentrations of the cathepsin inhibitors CA-074 (A) or pepstatin (B) and then treated with vehicle or with C2-Cer for 6 h. Bars depict the percentage of viability (mean ± SEM) compared to controls. ns, non-significant statistical differences. (PNG 305 kb)

12035_2018_1402_MOESM1_ESM.tiff (40.6 mb)
High Resolution Image (TIFF 41611 kb)
12035_2018_1402_Fig11_ESM.png (183 kb)
Supplementary Fig. 2

Neither programmed necrosis nor autophagy were involved in C2-Cer-induced photoreceptor death. A, Bars depict the percentage of LDH release compared to controls in cultures treated or not with C2-Cer for 6 h. Cultures treated with 350 μM Hydrogen Peroxide for 6 h were used as positive controls; culture media without contact with cells were used as negative controls. B, C, D, Bars represent the percentage of viability compared to controls (mean ± SEM) in cultures pretreated with different concentrations of necrostatin-1 (Nec-1), 3-MA or Bafilomycin 1 (BafA1) respectively, and then treated with vehicle or with C2-Cer for 6 h. (PNG 183 kb)

12035_2018_1402_MOESM2_ESM.tiff (22.1 mb)
High Resolution Image (TIFF 22662 kb)


  1. 1.
    Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809. CrossRefPubMedGoogle Scholar
  2. 2.
    Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–150. CrossRefPubMedGoogle Scholar
  3. 3.
    Rotstein NP, Miranda GE, Abrahan CE, German OL (2010) Regulating survival and development in the retina: key roles for simple sphingolipids. J Lipid Res 51:1247–1262. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Young MM, Kester M, Wang H-G (2013) Sphingolipids: regulators of crosstalk between apoptosis and autophagy. J Lipid Res 54:5–19. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    German OL, Miranda GE, Abrahan CE, Rotstein NP (2006) Ceramide is a mediator of apoptosis in retina photoreceptors. Invest Ophthalmol Vis Sci 47:1658–1668. CrossRefPubMedGoogle Scholar
  6. 6.
    Sanvicens N, Cotter TG (2006) Ceramide is the key mediator of oxidative stress-induced apoptosis in retinal photoreceptor cells. J Neurochem 98:1432–1444. CrossRefPubMedGoogle Scholar
  7. 7.
    Ranty M-L, Carpentier S, Cournot M, Rico-Lattes I, Malecaze F, Levade T, Delisle M-B, Quintyn J-C (2009) Ceramide production associated with retinal apoptosis after retinal detachment. Graefes Arch Clin Exp Ophthalmol 247:215–224. CrossRefPubMedGoogle Scholar
  8. 8.
    Fan J, Wu BX, Crosson CE (2016) Suppression of acid sphingomyelinase protects the retina from ischemic injury. Investig Opthalmol Vis Sci 57:4476–4484. CrossRefGoogle Scholar
  9. 9.
    Strettoi E, Gargini C, Novelli E, Sala G, Piano I, Gasco P, Ghidoni R (2010) Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa. Proc Natl Acad Sci U S A 107:18706–18711. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chen H, Tran J-TA, Eckerd A, Huynh T-P, Elliott MH, Brush RS, Mandal NA (2013) Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration. J Lipid Res 54:1616–1629. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Stiles M, Qi H, Sun E, Tan J, Porter H, Allegood J, Chalfant CE, Yasumura D et al (2016) Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration. J Lipid Res 57:818–831. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Scarlatti F, Bauvy C, Ventruti A, Sala G, Cluzeaud F, Vandewalle A, Ghidoni R, Codogno P (2004) Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem 279:18384–18391. CrossRefPubMedGoogle Scholar
  13. 13.
    Sims K, Haynes CA, Kelly S, Allegood JC, Wang E, Momin A, Leipelt M, Reichart D et al (2010) Kdo2-lipid A, a TLR4-specific agonist, induces de novo sphingolipid biosynthesis in RAW264.7 macrophages, which is essential for induction of autophagy. J Biol Chem 285:38568–38579. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Saddoughi SA, Gencer S, Peterson YK, Ward KE, Mukhopadhyay A, Oaks J, Bielawski J, Szulc ZM et al (2013) Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol Med 5:105–121. CrossRefPubMedGoogle Scholar
  15. 15.
    Politi LE, Lehar M, Adler R (1988) Development of neonatal mouse retinal neurons and photoreceptors in low density cell culture. Invest Ophthalmol Vis Sci 29:534–543PubMedGoogle Scholar
  16. 16.
    Adler R (1982) Regulation of neurite growth in purified retina neuronal cultures: effects of PNPF, a substratum-bound, neurite-promoting factor. J Neurosci Res 8:165–177. CrossRefPubMedGoogle Scholar
  17. 17.
    Ji L, Zhang G, Uematsu S, Akahori Y, Hirabayashi Y (1995) Induction of apoptotic DNA fragmentation and cell death by natural ceramide. FEBS Lett 358:211–214. CrossRefPubMedGoogle Scholar
  18. 18.
    Jordán J, Galindo MF, Prehn JH, Weichselbaum RR, Beckett M, Ghadge GD, Roos RP, Leiden JM et al (1997) P53 expression induces apoptosis in hippocampal pyramidal neuron cultures. J Neurosci 17:1397–1405. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. CrossRefGoogle Scholar
  20. 20.
    Rotstein NP, Politi LE, German OL, Girotti R (2003) Protective effect of docosahexaenoic acid on oxidative stress-induced apoptosis of retina photoreceptors. Investig Ophthalmol Vis Sci 44:2252–2259. CrossRefGoogle Scholar
  21. 21.
    Sánchez Campos S, Rodríguez Diez G, Oresti GM, Salvador GA (2015) Dopaminergic neurons respond to iron-induced oxidative stress by modulating lipid acylation and deacylation cycles. PLoS One 10:1–20. CrossRefGoogle Scholar
  22. 22.
    Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685. CrossRefPubMedGoogle Scholar
  23. 23.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E et al (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446. CrossRefPubMedGoogle Scholar
  24. 24.
    Ruchalski K, Mao H, Li Z, Wang Z, Gillers S, Wang Y, Mosser DD, Gabai V et al (2006) Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation. J Biol Chem 281:7873–7880. CrossRefPubMedGoogle Scholar
  25. 25.
    Yu S-W, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, Dawson VL (2006) Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci 103:18314–18319. CrossRefPubMedGoogle Scholar
  26. 26.
    Wang Y, Kim NS, Li X, Greer PA, Koehler RC, Dawson VL, Dawson TM (2009) Calpain activation is not required for AIF translocation in PARP-1-dependent cell death (parthanatos). J Neurochem 110:687–696. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yuste VJ, Moubarak RS, Delettre C, Bras M, Sancho P, Robert N, d’Alayer J, Susin SA (2005) Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release. Cell Death Differ 12:1445–1448. CrossRefPubMedGoogle Scholar
  28. 28.
    Polster BM, Basañez G, Etxebarria A, Hardwick JM, Nicholls DG (2005) Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J Biol Chem 280:6447–6454. CrossRefPubMedGoogle Scholar
  29. 29.
    Douglas DL, Baines CP (2014) PARP1-mediated necrosis is dependent on parallel JNK and Ca2+/calpain pathways. J Cell Sci 127:4134–4145. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Jiang H-Y, Yang Y, Zhang Y-Y, Xie Z, Zhao X-Y, Sun Y, Kong W-J (2018) The dual role of poly(ADP-ribose) polymerase-1 in modulating parthanatos and autophagy under oxidative stress in rat cochlear marginal cells of the stria vascularis. Redox Biol 14:361–370. CrossRefPubMedGoogle Scholar
  31. 31.
    Piano I, Novelli E, Gasco P, Ghidoni R, Strettoi E, Gargini C (2013) Cone survival and preservation of visual acuity in an animal model of retinal degeneration. Eur J Neurosci 37:1853–1862. CrossRefPubMedGoogle Scholar
  32. 32.
    Stoica BA, Movsesyan VA, Lea PM, Faden AI (2003) Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci 22:365–382. CrossRefPubMedGoogle Scholar
  33. 33.
    Kim NH, Kim K, Park WS, Son HS, Bae Y (2007) PKB/Akt inhibits ceramide-induced apoptosis in neuroblastoma cells by blocking apoptosis-inducing factor (AIF) translocation. J Cell Biochem 102:1160–1170. CrossRefPubMedGoogle Scholar
  34. 34.
    Siskind LJ, Kolesnick RN, Colombini M (2002) Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J Biol Chem 277:26796–26803. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Siskind LJ, Davoody A, Lewin N, Marshall S, Colombini M (2003) Enlargement and contracture of C2-ceramide channels. Biophys J 85:1560–1575. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Stoica BA, Movsesyan VA, Knoblach SM, Faden AI (2005) Ceramide induces neuronal apoptosis through mitogen-activated protein kinases and causes release of multiple mitochondrial proteins. Mol Cell Neurosci 29:355–371. CrossRefPubMedGoogle Scholar
  37. 37.
    Colombini M (2010) Ceramide channels and their role in mitochondria-mediated apoptosis. Biochim Biophys Acta 1797:1239–1244. CrossRefPubMedGoogle Scholar
  38. 38.
    Di Paola M, Cocco T, Lorusso M (2000) Ceramide interaction with the respiratory chain of heart mitochondria . Biochemistry 39:6660–6668. CrossRefPubMedGoogle Scholar
  39. 39.
    Pettus BJ, Chalfant CE, Hannun YA (2002) Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta Mol Cell Biol Lipids 1585:114–125. CrossRefGoogle Scholar
  40. 40.
    Bidère N, Lorenzo HK, Carmona S, Laforge M, Harper F, Dumont C, Senik A (2003) Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis. J Biol Chem 278:31401–31411. CrossRefPubMedGoogle Scholar
  41. 41.
    Ganesan V, Perera MN, Colombini D, Datskovskiy D, Chadha K, Colombini M (2010) Ceramide and activated Bax act synergistically to permeabilize the mitochondrial outer membrane. Apoptosis 15:553–562. CrossRefPubMedGoogle Scholar
  42. 42.
    Gudz TI, Tserng KY, Hoppel CL (1997) Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem 272:24154–24158. CrossRefPubMedGoogle Scholar
  43. 43.
    García-Ruiz C, Colell A, Marí M, Morales A, Fernández-Checa JC (1997) Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biol Chem 272:11369–11377. CrossRefPubMedGoogle Scholar
  44. 44.
    Fan C, Liu Y, Zhao M, Zhan R, Cui W, Jin H, Teng Y, Lv P et al (2017) Autophagy inhibits C2-ceramide-mediated cell death by decreasing the reactive oxygen species levels in SH-SY5Y cells. Neurosci Lett 651:198–206. CrossRefPubMedGoogle Scholar
  45. 45.
    Falluel-Morel A, Aubert N, Vaudry D, Basille M, Fontaine M, Fournier A, Vaudry H, Gonzalez BJ (2004) Opposite regulation of the mitochondrial apoptotic pathway by C2-ceramide and PACAP through a MAP-kinase-dependent mechanism in cerebellar granule cells. J Neurochem 91:1231–1243. CrossRefPubMedGoogle Scholar
  46. 46.
    Donovan M, Cotter TG (2002) Caspase-independent photoreceptor apoptosis in vivo and differential expression of apoptotic protease activating factor-1 and caspase-3 during retinal development. Cell Death Differ 9:1220–1231. CrossRefPubMedGoogle Scholar
  47. 47.
    Donovan M, Doonan F, Cotter TG (2006) Decreased expression of pro-apoptotic Bcl-2 family members during retinal development and differential sensitivity to cell death. Dev Biol 291:154–169. CrossRefPubMedGoogle Scholar
  48. 48.
    Lohr HR, Kuntchithapautham K, Sharma AK, Rohrer B (2006) Multiple, parallel cellular suicide mechanisms participate in photoreceptor cell death. Exp Eye Res 83:380–389. CrossRefPubMedGoogle Scholar
  49. 49.
    Yoshizawa K, Kiuchi K, Nambu H, Yang J, Senzaki H, Kiyozuka Y, Shikata N, Tsubura A (2002) Caspase-3 inhibitor transiently delays inherited retinal degeneration in C3H mice carrying the rd gene. Graefes Arch Clin Exp Ophthalmol 240:214–219. CrossRefPubMedGoogle Scholar
  50. 50.
    Doonan F, Donovan M, Cotter TG (2005) Activation of multiple pathways during photoreceptor apoptosis in the rd mouse. Invest Ophthalmol Vis Sci 46:3530–3538. CrossRefPubMedGoogle Scholar
  51. 51.
    Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL et al (2012) Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012. Cell Death Differ 19:107–120. CrossRefPubMedGoogle Scholar
  52. 52.
    Andrabi SA, Dawson TM, Dawson VL (2008) Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann N Y Acad Sci 1147:233–241. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Narne P, Pandey V, Simhadri PK, Phanithi PB (2017) Poly(ADP-ribose)polymerase-1 hyperactivation in neurodegenerative diseases: the death knell tolls for neurons. Semin Cell Dev Biol 63:154–166. CrossRefPubMedGoogle Scholar
  54. 54.
    Hong SJ, Dawson TM, Dawson VL (2004) Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci 25:259–264. CrossRefPubMedGoogle Scholar
  55. 55.
    Schreiber V, Amé J-C, Dollé P, Schultz I, Rinaldi B, Fraulob V, Ménissier-de Murcia J, de Murcia G (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277:23028–23036. CrossRefPubMedGoogle Scholar
  56. 56.
    Ying W, Garnier P, Swanson RA (2003) NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes. Biochem Biophys Res Commun 308:809–813. CrossRefPubMedGoogle Scholar
  57. 57.
    Andrabi SA, Umanah GKE, Chang C, Stevens DA, Karuppagounder SS, Gagné J-P, Poirier GG, Dawson VL et al (2014) Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc Natl Acad Sci U S A 111:10209–10214. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Wang Y, Dawson VL, Dawson TM (2009) Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol 218:193–202. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Baek S-H, Bae O-N, Kim E-K, Yu S-W (2013) Induction of mitochondrial dysfunction by poly(ADP-ribose) polymer: implication for neuronal cell death. Mol Cell 36:258–266. CrossRefGoogle Scholar
  60. 60.
    Paquet-Durand F, Silva J, Talukdar T, Johnson LE, Azadi S, van Veen T, Ueffing M, Hauck SM et al (2007) Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse. J Neurosci 27:10311–10319. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Sahaboglu A, Sharif A, Feng L, Secer E, Zrenner E, Paquet-Durand F (2017) Temporal progression of PARP activity in the Prph2 mutant rd2 mouse: neuroprotective effects of the PARP inhibitor PJ34. PLoS One 12:e0181374. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Stiban J, Perera M (2015) Very long chain ceramides interfere with C16-ceramide-induced channel formation: a plausible mechanism for regulating the initiation of intrinsic apoptosis. Biochim Biophys Acta Biomembr 1848:561–567. CrossRefGoogle Scholar
  63. 63.
    Hernández-Corbacho MJ, Canals D, Adada MM, Liu M, Senkal CE, Yi JK, Mao C, Luberto C et al (2015) Tumor necrosis factor-α (TNFα)-induced ceramide generation via ceramide synthases regulates loss of focal adhesion kinase (FAK) and programmed cell death. J Biol Chem 290:25356–25373. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Chiang SK, Lam TT (2000) Post-treatment at 12 or 18 hours with 3-aminobenzamide ameliorates retinal ischemia-reperfusion damage. Invest Ophthalmol Vis Sci 41:3210–3214PubMedGoogle Scholar
  65. 65.
    Goebel DJ, Winkler BS (2006) Blockade of PARP activity attenuates poly(ADP-ribosyl)ation but offers only partial neuroprotection against NMDA-induced cell death in the rat retina. J Neurochem 98:1732–1745. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Miki K, Uehara N, Shikata N, Matsumura M, Tsubura A (2007) Poly (ADP-ribose) polymerase inhibitor 3-aminobenzamide rescues N-methyl-N-nitrosourea-induced photoreceptor cell apoptosis in Sprague-Dawley rats through preservation of nuclear factor-kappaB activity. Exp Eye Res 84:285–292. CrossRefPubMedGoogle Scholar
  67. 67.
    Sahaboglu A, Barth M, Secer E, del Amo EM, Urtti A, Arsenijevic Y, Zrenner E, Paquet-Durand F (2016) Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration. Sci Rep 6:39537. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Spinedi A, Amendola A, Di Bartolomeo S, Piacentini M (1998) Ceramide-induced apoptosis is mediated by caspase activation independently from retinoblastoma protein post-translational modification. Biochem Biophys Res Commun 243:852–857. CrossRefPubMedGoogle Scholar
  69. 69.
    Flowers M, Fabriás G, Delgado A, Casas J, Abad JL, Cabot MC (2012) C6-ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth. Breast Cancer Res Treat 133:447–458. CrossRefPubMedGoogle Scholar
  70. 70.
    Kota V, Dhople VM, Fullbright G, Smythe NM, Szulc ZM, Bielawska A, Hama H (2013) 2′-Hydroxy C16-ceramide induces apoptosis-associated proteomic changes in C6 glioma cells. J Proteome Res 12:4366–4375. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Xu R, Wang K, Mileva I, Hannun YA, Obeid LM, Mao C (2016) Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response. Oncotarget 7:18440–18457. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Czubowicz K, Strosznajder R (2014) Ceramide in the molecular mechanisms of neuronal cell death. The role of sphingosine-1-phosphate. Mol Neurobiol 50:26–37. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Otera H, Ohsakaya S, Nagaura Z-I, Ishihara N, Mihara K (2005) Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. EMBO J 24:1375–1386. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Sanges D, Comitato A, Tammaro R, Marigo V (2006) Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors. Proc Natl Acad Sci 103:17366–17371. CrossRefPubMedGoogle Scholar
  75. 75.
    Andrabi SA, Kim NS, Yu S-W, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T et al (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci 103:18308–18313. CrossRefPubMedGoogle Scholar
  76. 76.
    Wang Y, Kim NS, Haince J-F, Kang HC, David KK, Andrabi SA, Poirier GG, Dawson VL et al (2011) Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Sci Signal 4:ra20. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Cao G, Xing J, Xiao X, Liou AKF, Gao Y, Yin X-M, Clark RSB, Graham SH et al (2007) Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. J Neurosci 27:9278–9293. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Yang Q, Zhang C, Wei H, Meng Z, Li G, Xu Y, Chen Y (2017) Caspase-independent pathway is related to nilotinib cytotoxicity in cultured cardiomyocytes. Cell Physiol Biochem 42:2182–2193. CrossRefPubMedGoogle Scholar
  79. 79.
    Czerwinski A, Basava C, Dauter M, Dauter Z (2015) Crystal structure of N-{N-[N-acetyl-(S)-leuc-yl]-(S)-leuc-yl}norleucinal (ALLN), an inhibitor of proteasome. Acta Crystallogr Sect E Crystallogr Commun 71:254–257. CrossRefGoogle Scholar
  80. 80.
    Moubarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA, Menissier-de Murcia J, Susin SA (2007) Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol Cell Biol 27:4844–4862. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Bailey LJ, Alahari S, Tagliaferro A, Post M, Caniggia I (2017) Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis. Cell Death Dis 8:e2590–e2590. CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Jouan-Lanhouet S, Arshad MI, Piquet-Pellorce C, Martin-Chouly C, Le Moigne-Muller G, Van Herreweghe F, Takahashi N, Sergent O et al (2012) TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. Cell Death Differ 19:2003–2014. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Aredia F, Scovassi AI (2014) Involvement of PARPs in cell death. Front Biosci (Elite Ed) 6:308–317CrossRefGoogle Scholar
  84. 84.
    Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714. CrossRefPubMedGoogle Scholar
  85. 85.
    Aredia F, Scovassi AI (2014) Poly(ADP-ribose): a signaling molecule in different paradigms of cell death. Biochem Pharmacol 92:157–163. CrossRefPubMedGoogle Scholar
  86. 86.
    Morris G, Walker AJ, Berk M, Maes M, Puri BK (2017) Cell death pathways: a novel therapeutic approach for neuroscientists. Mol Neurobiol 55:5767–5786. CrossRefPubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Instituto de Investigaciones Bioquímicas, Depto. de Biología, Bioquímica y FarmaciaUniversidad Nacional del Sur (UNS)-CONICETBahía BlancaArgentina

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