Retinis pigmentosastudy of neurodegenerative processes and development of experimental therapies in the rdl mouse model of inherited retinal degeneration

Laburpena

Abstract Retinitis Pigmentosa (RP) is a genetically heterogeneous family of inherited diseases that result in photoreceptor cell death and blindness. Loss of photoreceptors leads to typical clinical symptoms: night blindness, tunnel vision, and accumulation of pigment deposits. RP is at present untreatable and the underlying neurodegenerative mechanisms remain unknown even though the genetic causes are often established. The best characterized animal model for the study of RP, the rd1 mouse, carries a mutation in the PDE6 gene of rod photoreceptors. This non-functional PDE6 produces an accumulation of cGMP which ultimately results in photoreceptor cell death. Secondary mutation-independent cone cell death also occurs. In this study, two different approaches were carried out to further elucidate retinal degeneration processes in the rd1 mouse. Initially, the implications of the immune system in secondary cone cell death were considered. To that end, expression of sialoadhesin (Sn) ¿ a cell surface protein expressed by subpopulations of macrophages and microglia ¿ was analyzed before and after transplantation. It appeared that activated microglia within the retina did not express Sn. When a graft was subretinally implanted, host originating Sn-expressing cells, characterized as macrophages, were found in the area. For the second approach, levels of core histone acetylation ¿ a post-transcriptional change that may alter gene-transcription without changing DNA sequence ¿ were measured in rd1 retina to explore epigenetic involvements in the degenerative process. Results showed that there is histone hypoacetylation in dying cells. This was linked to overactive histone deacetylases (HDACs) observed in degenerating photoreceptors. Consequently, pharmacological inhibition of HDACs class I and II in organotypic retinal explants significantly reduced photoreceptor cell death