Retinitis pigmentosa (RP) is a genetic degenerative disease causing blindness in later life. About 50 genes have been linked to this hereditary disease and this genetic heterogeneity represents a major impediment to the development therapies. 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. We studied the rd1, the Rho-/- and the P23H transgenic mouse models with immunocytochemical, molecular 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. 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. Aif appears to play a fundamental role in different forms of retinal degeneration. Otherwise, ER stress pathways do not appear to be activated in all models analyzed. 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.
TARGETING CELL DEATH PATHWAYS ACTIVATED IN MURINE MODELS OF RETINITIS PIGMENTOSA / Comitato, Antonella; Marigo, Valeria. - (2012), pp. 21-21.
|Data di pubblicazione:||2012|
|Titolo:||TARGETING CELL DEATH PATHWAYS ACTIVATED IN MURINE MODELS OF RETINITIS PIGMENTOSA|
|Autore/i:||Comitato, Antonella; Marigo, Valeria|
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