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Francois Paquet-Durand, Sandra Bernhard-Kurz, Blanca Arango-Gonzalez, Eberhart Zrenner, Marius Ueffing; Cell Death in rd2/rds Retina: An Apoptotic Process?. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6891.
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© ARVO (1962-2015); The Authors (2016-present)
Apoptosis has been accepted for a long time as the prevalent mechanism governing inherited photoreceptor degeneration in retinal degeneration (RD). However, in many human homologous animal models for RD characteristic markers for apoptosis are absent. Here, we demonstrate a non-apoptotic cell death mechanism in the rd2/rds mouse model for rod-cone dystrophy.
Analysing cell death in rd2/rds mutant mice, as well as congenic wild-types in situ, we applied enzyme activity assays and immunohistochemistry to quantify expression, topology, and temporal dynamics of markers for apoptosis (BAX expression, cytochrome-c leakage, activities of caspase-9, -3) and for non-apoptotic cell death (cGMP, activities of protein kinase G (PKG), histone deacetylase (HDAC), poly-ADP-ribose-polymerase (PARP), calpain). Organotypic retinal explant cultures were used for pharmacological interventions.
Compared with other RD models (e.g. rd1 mice) the rd2/rds photoreceptor degeneration displays a later onset and progresses more slowly. Cell death peaks at post-natal day 18. In rd2/rds retina, photoreceptor cGMP-levels and non-apoptotic death markers (PKG, calpain, PARP, and HDAC activity) were clearly increased in both rods and cones, while apoptotic markers were restricted to early post-natal developmental cell death. Pharmacological inhibition of PKG could attenuate degeneration, demonstrating the functional involvement of PKG in rd2/rds induced photoreceptor death.
Our study demonstrates that non-apoptotic cell death is the prevalent molecular mechanism executing rd2/rds degeneration: Based on recent results obtained in other RD animal models (Kaur et al., 2011), we propose an alternative cell death pathway connected to excessive cGMP signalling, and followed by consecutive activation of PKG, HDAC, PARP, and calpain in rd2/rds rod and cone photoreceptors. As this pathway is common to several different types of mutations causing RD, nodes and edges (e.g. epigenetic events or calpain activity) within this metabolic network triggered by cGMP signalling may provide novel targets for mutation-independent interventions into RD.
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