Caspase-Independent Photoreceptor Apoptosis in Mouse Models of Retinal Degeneration
TLDR
It is found that cytochrome c-dependent proteolysis and activation of caspase-9 could not be restored in an adult cell-free system because of an age-related decrease in the expression of Apaf-1 in the normal developing mouse retina.Abstract:
Apoptosis is the mode of cell death in retinitis pigmentosa, a group of retinal degenerative disorders primarily affecting rod photoreceptors. Although caspases have been demonstrated to play a central role in many incidences of apoptosis, accumulating evidence suggests that they may not be required for all forms of apoptotic cell death. The present study examined the mechanism of cell death in two in vivo models of photoreceptor apoptosis: the retinal degeneration (rd) mouse, a naturally occurring mutant model, and N-methyl-N-nitrosourea-induced retinal degeneration. Specifically, we examined the activation status of caspase-9, -8, -7, -3, and -2 and determined the caspase requirements for cytochrome c release, DNA fragmentation, and apoptosis-associated proteolysis of specific caspase substrates. We show that apoptosis in both in vivo models is independent of caspase-9, -8, -7, -3, and -2 activation. DNA fragmentation occurs in the absence of caspase-mediated ICAD (inhibitor of caspase-activated DNase) proteolysis, suggesting that an alternative endonuclease is responsible for DNA cleavage in these models. Importantly, we show that apoptosome activation is prevented because of an absence of mitochondrial cytochrome c release. Experiments performed using a cell-free system indicate that cytochrome c-dependent proteolysis and activation of caspase-9 can be restored in a neonatal cell-free system. However, we found that cytochrome c-dependent proteolysis and activation of caspase-9 could not be restored in an adult cell-free system because of an age-related decrease in the expression of Apaf-1 in the normal developing mouse retina. In the rd mouse, however, this age-related downregulation of apoptotic proteins was not observed, highlighting a critical feature of this model and the prevention of cytochrome c release as an apical event in caspase-independent apoptosis in this system.read more
Citations
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Journal ArticleDOI
Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration.
TL;DR: An overview on molecular and cellular mechanisms of apoptosis and recent developments is presented and a vast array of different neuroprotective cytokines that are applied in light-damage and RP animal models and show diverging efficacy are described.
Journal ArticleDOI
Photoreceptor Cell Death Mechanisms in Inherited Retinal Degeneration
Javier Sancho-Pelluz,Blanca Arango-Gonzalez,Stefan Kustermann,Francisco J. Romero,Theo van Veen,Eberhart Zrenner,Per Ekström,François Paquet-Durand +7 more
TL;DR: A putative non-apoptotic molecular pathway for photoreceptor cell death in the rd1 retina is proposed based on recent experimental evidence and may provide new ideas for future treatment of RP.
Journal ArticleDOI
Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death.
TL;DR: This review will focus on the regulation of mitochondrial integrity by Bcl-2 family members with particular attention to the controlled release of factors involved in caspase-independent cell death.
Journal ArticleDOI
Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors.
TL;DR: It is shown that two apoptotic pathways are coactivated during the degenerative process in an animal model of retinitis pigmentosa, the rd1 mouse, and that AIF plays the major role in this apoptotic event, whereas caspase-12 has a reinforcing effect.
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