Mechanism of photoreceptor cell degeneration in animal models of retinal disease

University Of Oklahoma Hlth Sciences Ctr, Oklahoma City OK

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Abstract

DESCRIPTION (provided by applicant): Retinal degeneration slow (RDS) is a photoreceptor-specific glycoprotein critical for rod and cone outer segment (OS) rim formation and maintenance. Rim formation is critical for OS structure; in the absence of RDS no rod OSs are formed and no rod function is detected while cones develop dysmorphic balloon-like OSs that lack lamellae but contain cone opsins and retain ~50% of function. Developing a thorough understanding of the role and function of RDS in rods and cones is critical as over 100 different mutations in RDS cause retinal degenerative diseases with widely varying phenotypes including rod-dominant autosomal dominant retinitis pigmentosa (ADRP) and multiple classes of cone-dominant macular dystrophy (MD). Studies have suggested that mutations that cause rod-dominant disease result in null alleles likely due to protein misfolding while mutations that cause cone-dominant disease have a more complex pathology. Assessment of disease in patients has shown that in many cases, RDS-associated macular vision loss is not only associated with primary defects in photoreceptors, but with subsequent secondary toxicity and changes in the retinal pigment epithelium (RPE) and choroidal/retinal vasculature. Nothing is known about the link between these primary defects and the blinding secondary sequellae; however, for the first time we have generated mouse models which facilitate study of this issue. The diversity in RDS-associated phenotypes seen in patients coupled with data from cone and rod- dominant mouse models suggests that rods and cones have different requirements for RDS. It is not clear why these two cell types should be so differently affected by different mutations, primarily because our current knowledge of the precise function of RDS in these two cell types is incomplete. Here we plan to focus our investigation on understanding how RDS functions differently in rods and cones with particular interest in RDS initial complex formation and trafficking, role in cone vs. rod OS structures, and effects of RDS mutations on overall retinal health. We will conduct a careful assessment of the molecular properties of RDS and RDS mutants, with specific regard to complex assembly in the IS and trafficking to the OS in Aim 1; and study the role of RDS in OS structures, disc/rim formation, and disc sizing in Aim 2. Of particular interest will be differences in these processes between rods and cones. Links between RDS-mutation-associated photoreceptor defects and alterations in the RPE and choroid will be assessed in Aim 3. We have a set of unique tools at our disposal and advanced genetically engineered mouse models to study how mutations in RDS result in diverse retinal pathologies as a consequence of abnormal OS formation and the role of RDS in the closed rim structure in rods and the open rim structures in cones. Given the lack of effective treatments for RDS-associated disease these studies are essential.