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D. Trifunovic, K. Dengler, S. Michalakis, E. Zrenner, B. Wissinger, F. Paquet-Durand; Mechanisms of Cone Photoreceptor Cell Death in the cpfl1 Mouse. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3668. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Understanding the mechanisms of cell death during inherited retinal degeneration may allow the definition of novel targets for neuroprotection. The rd1 mouse is one of the best characterized animal models for rod photoreceptor degeneration, while the cpfl1 mouse is a recently discovered model for cone cell death. Since both animal models are affected by functionally similar mutations in the rod and cone phosphodiesterase 6 genes, respectively, we asked whether photoreceptor degeneration in these two mouse lines follows similar pathways.
In the present study, we assessed the temporal progression of photoreceptor degeneration in the cpfl1 retina, correlated it with specific metabolic markers and compared it with the wild-type and the rd1 situation using immunohistological approaches and in situ activity assays.
Similar to corresponding rd1 observations, cpfl1 cone photoreceptor cell death is associated with an accumulation of cGMP, activity of calpains and protein kinase G, and phosphorylation of VASP. Conversely, increased oxidative stress, PARP activity and HDAC activity were detected only in rd1 but not in cpfl1 mice. Cone degeneration in cpfl1 mice was characterized by early onset (PN14) and rapid progression. Furthermore, cpfl1 cone photoreceptor migration during early post-natal development was delayed significantly when compared to the corresponding wild-type retina
The finding that rod and cone photoreceptor degeneration was associated with the same metabolic markers suggests the existence of a cell death mechanism common to both rod and cone degeneration. This raises the possibility that equivalent neuroprotective strategies may be used to prevent both types of photoreceptor degeneration. On the other hand, the absence of oxidative stress, PARP and HDAC activity in cpfl1 retina proposes that these are epiphenomena due to massive rod cell death in rd1 retina.
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