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V. Marigo, A. Comitato, C. Aruta, A. Rossi, G. De Feo, A. De Marzo, F. Della Valle; Molecular Pathways Activated During Apoptosis in Murine Models of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2942.
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Molecular mechanisms underlying apoptosis in retinitis pigmentosa (RP) are still elusive and this hampers the development of a cure for this blinding disease. A better characterization of molecular events underlying rod cell demise can help in identifying new targets for therapeutic interventions aimed at restraining or stop cell death.
We undertook co-localization studies by immunofluorescence and activity assays of several factors involved in cell death. We analyzed mitochondrial AIF, caspase-12, caspase-3, calpain activation and ER stress markers in rd1 mice, P23H transgenic mice and rhodopsin knock-out mice.
We found calpain activation in the three models. siRNA experiments down-regulating either calpain 1 or calpain 2 allowed to define the different contributions of these two proteases. AIF and caspase-12 are activated and translocate to the nucleus in rd1 dying rods. By reduction of AIF expression we confirmed the important role of AIF in apoptosis in the rd1 retina. AIF appears also to be important for other forms of retinal degeneration. Activation of ER markers was analyzed in the three murine models.
The option of exploiting apoptosis as a therapeutic target is complex. Nevertheless the molecular understanding of the apoptotic factors activated during degeneration and the identification of common activators are the first step toward this goal. Our study identifies AIF as a key factor triggering photoreceptor cell demise. 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.
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