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V. Marigo, D. Sanges, A. Comitato; Common Apoptotic Mechanisms in Different Forms of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4946. doi: https://doi.org/.
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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. Changes in intracellular calcium homeostasis had been associated with retinal degeneration in the rd1 mouse. Retention of mutant protein in the endoplasmic reticulum (ER) was shown to have detrimental effects in transgenic mice expressing mutant rhodopsin. AIF and caspase-12 are activated by calpains in response to ER stress caused by either protein misfolding or disruption of calcium homeostasis.
In order to correlate activation of mitochondrial AIF, caspase-12 and apoptosis, co-localization studies by triple immunofluorescence of AIF, caspase-12 and TUNEL were undertaken in sections of degenerating retinas. Similar experiments were performed in wild type and mutant retinal stem cells differentiated in vitro to rod photoreceptors. Retinal stem cells were treated with calpain inhibitors, caspase inhibitors, siRNAs targeting AIF, caspase-12 and calpains followed by immunofluorescence analysis. P10 mutant mice were intravitreally injected with either calpain inhibitors or caspase inhibitors and the outcome was evaluated by immunoflorescence and TUNEL staining at different time points.
We found that AIF and caspase-12 are activated and localize to the nucleus of the same apoptotic photoreceptors in the two murine models for RP. By reduction of AIF or caspase-12 expression we also defined that AIF plays the major role in apoptosis in the rd1 retina while caspase-12 is more important when apoptosis is triggered by protein misfolding. In both events calpains are activated and interference with their activity slows or block apoptosis.
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 and caspase-12 as two apoptotic factors 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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