Ceramide induces the death of retina photoreceptors through activation of parthanatos

PRADO SPALM F.H.; VERA MS; DIBO MJ; SIMON, M.V.; POLITI LE ; ROTSTEIN NP

Córdoba

Congreso; XXXIII Reunión Anual de la SAN; 2018

SAN

Ceramide induces the death of retina photoreceptors through activation of parthanatosFacundo H. Prado Spalm, Marcela S. Vera, Marcos J. Dibo, M. Victoria Simón, Luis E. Politi and Nora P. Rotstein. Instituto de Investigaciones Bioquímicas, Depto. de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, 8000 Bahía Blanca, Buenos Aires, Argentina. inrotste@criba.edu.arCeramide (Cer) 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. 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. increased polyADP ribose polymer (PAR) levels and induced the nuclear translocation of apoptosis inducing factor (AIF). Inhibiting PARP-1 decreased C2-Cer induced photoreceptor death and prevented AIF translocation. 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 were involved in C2-Cer-elicited death. 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, which are all biochemical features of parthanatos.