Regulation of survival and development of retina photoreceptors by sphingolipids

ROTSTEIN N.P.; MIRANDA G.E.; ABRAHAN C.E.

Búzios, Rio de Janeiro, Brasil

Congreso; 1er. Congreso IBRO/LARC de América Latina, Caribe y Península Ibérica, Neurolatam; 2008

Neurolatam, IBRO-LARC

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman";} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:35.4pt; mso-footer-margin:35.4pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> REGULATION OF SURVIVAL AND DEVELOPMENT OF RETINA PHOTORECEPTORS BY SPHINGOLIPIDS Nora Rotstein, Gisela Miranda and Carolina Abrahan. Instituto de Investigaciones Bioquímicas, Bahía Blanca, Argentina  Photoreceptor apoptosis is a hallmark of neurodegenerative diseases leading to blindness. Since the finding of stem cells in the retina, uncovering cell signals that induce these cells to proliferate and differentiate to replace lost neurons or block cell death are the most promising strategies for preserving retina functionality. The sphingolipid sphingosine-1-phosphate (S1P) promotes survival and proliferation in several cell systems, but its role in the retina is unknown. We have here investigated whether S1P might regulate photoreceptor survival, proliferation and differentiation. Addition of S1P or docosahexaenoic acid (DHA), which promotes photoreceptor survival, to rat retina neuronal cultures prevented photoreceptor apoptosis induced by oxidative stress, while inhibiting sphingosine kinase (SK), the enzyme required for S1P synthesis, blocked DHA protection. S1P also stimulated neuroblast proliferation; its early addition to neuronal cultures increased several markers of cell cycle progression. In addition, S1P stimulated photoreceptor differentiation. We have previously reported that DHA promotes photoreceptor differentiation; S1P effects were remarkably similar to those of DHA; it enhanced opsin and peripherin expression and the formation of apical processes where both proteins were highly localized. Inhibiting S1P synthesis blocked DHA effect on differentiation, which could be restored by S1P addition. Brefeldin A, which inhibits traffic from ER to Golgi, inhibited the formation of apical processes induced by S1P and DHA. These results suggest that DHA promotes the synthesis of S1P to stimulate survival and differentiation of photoreceptors. Investigating this hypothesis, we established that DHA enhanced the expression of SK in photoreceptors. S1P is both an extracellular and an intracellular messenger, and activates membrane receptors such as S1P3. Interestingly when the cultures were treated with BML-241, a S1P3 antagonist along with either S1P or DHA and then treated with the oxidant paraquat, BML-241 inhibited S1P antiapoptotic effect without affecting that of DHA. Hence, S1P might act as an extracellular signal, activating membrane receptors or as an intracellular signal, and trophic factors, such as DHA, might stimulate its synthesis, by promoting SK expression, to bring about their intracellular effects. In conclusion, our results suggest that S1P is a crucial mediator for the regulation of proliferation, survival and differentiation of photoreceptors.