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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
Article

Abstract

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.

Keywords

Photoreceptor death PARP Ceramide AIF Calpain Parthanatos 

Notes

Acknowledgements

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)

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

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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