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Dragana Trifunovic, Blanca Arango-Gonzalez, Klaudiaj Masarini, Norman Rieger, Michelle Dierstein, Marius Ueffing, Francois Paquet-Durand; HDAC inhibition protects degenerating cones in the cpfl1 mouse. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4035.
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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 cpfl1 mouse is a model for cone cell death characterized by fast and progressive cone degeneration. Additionally, the Pde6c mutation governing cpfl1 cone degeneration leads to an impaired cone migration during retinal developement by unknown mechanisms. The cpfl1 cone degeneration follows a non-apoptotic cell death mechanism and is characterized by cGMP accumulation and increased activities of PKG and calpains (Trifunovic et al., J Comp Neurol., 518(17):3604-17, 2010). In the present study, we asked whether the epigenetic modifications contributing to primary rod degeneration in Pde6b-mutant rd1 mice (Sancho-Pelluz et al., Cell Death Dis., 1:e24, 2010), are also involved in primary cone degeneration.
We assessed the correlation of increased HDAC activity and cone degeneration in cpfl1 retina using an HDAC in situ activity assay. The neuroprotective properties of the HDAC inhibitor, Trichostatin A (TSA), were assessed using a cpfl1 ex vivo retinal explant system, followed by immunohistological detection of characteristic cone markers.
Similar to corresponding observations in the rd1 model, cpfl1 cone photoreceptor cell death is associated with increased HDAC activity. TSA inhibition of the HDAC activity in cpfl1 retinal explant cultures resulted in a significant improvement in cone survival. At the same time, TSA treatment did not negatively affect wild-type cones. Notably, HDAC inhibition also significantly improved developmental cone migration compared to non-treated retinas.
Our finding that primary cone photoreceptor degeneration is associated with increased HDAC activity suggests the existence of cell death mechanisms 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. Indeed, HDAC inhibition emerges as a novel neuroprotective approach for the treatment of primary cone degeneration, and provides an exciting new possibility for a preservation of useful vision in patients suffering from cone dystrophies.
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