Cell death pathways activated in rod photoreceptors in different models of retinitis pigmentosa

Purpose: Retinitis pigmentosa (RP) is a genetic degenerative disease causing blindness in later life. About 50 genes have been linked to this hereditary disease. Heterogeneity of such magnitude in RP represents a major impediment to the development therapies, therefore mutation-independent approaches to target common molecular mechanisms activated during the degenerative process should be exploited. We molecularly characterized mitochondrial and ER pathways activated during rod cell death in three murine models of RP and developed molecules to interfere with their function. Methods: We studied the rd1, the Rho-/- and the P23H transgenic mouse models with molecular biology, immunocytochemical and biochemical approaches. We analyzed Aif, caspase-3 and caspase-7, Bax and Bak, calpain, cathepsin and ER stress markers. We performed in vitro interferences with shRNAs and in vivo treatments with Calpain, Cathepsin D and Bax inhibiting substances. Results: We found that calpains play a key role in the activation of Aif, Bax and cell death in the rd1 retina. shRNA experiments down-regulating either calpain 1 or calpain 2 allowed to define the different contributions of these two proteases. By reduction of Aif expression we confirmed the important role of Aif in apoptosis in the rd1 retina. Aif appears also to be important in the other forms of retinal degeneration. Otherwise, ER stress pathways do not appear to be activated in all models analyzed. Conclusions: The option of exploiting cell death as a therapeutic target is complex. Nevertheless the molecular understanding of the factors activated during degeneration and the identification of common activators are the first step toward this goal. Our study identifies calpains and Aif as a key factors triggering photoreceptor cell demise in the retina of different murine models of RP. The efficacy of interfering molecules targeting the different factors activated during the apoptotic cascade opens new perspectives for designing therapeutic approaches to rescue photoreceptor cell death in this disease.