maculopathy, malattia leventinese and Doyne Honeycomb Retinal Dystrophy (ML/DHRD) (Stone et al. 1999). Fibulin-3 encodes an extracellular protein that is expressed and secreted by retinal pigment epithelial (RPE) cells (Marmorstein et al. 2002). In cell culture studies, mutant R345W Fibulin-3 is inefficiently secreted, and the majority is retained in the ER (Roybal et al. 2005). UPR signaling pathways are activated leading to increased BiP/grp78 and VEGF production (Blais et al. 2006; Roybal et al. 2005). These findings support a model whereby mutant fibulin-3 leads to macular degeneration through its misfolding in the ER and activation of UPR signaling pathways in RPE cells, followed by enhanced VEGF production and choroidal neovascularization. Enhanced VEGF levels and choroidal neovascularization are also key features of AMD (Campochiaro 2007), raising the possibility that abnormal ER stress and UPR activity in RPE may also be at play in sporadic types of macular dystrophy.

14.4Pharmacologic Targeting of Protein Misfolding to Prevent Retinal Degeneration

Given the link between protein misfolding and retinal degeneration, most clearly established in the case of rhodopsin, pharmacologic prevention of protein misfolding has emerged as an exciting new strategy to treat these diseases. Chaperones are ubiquitous proteins dedicated to folding and stabilizing proteins, and recent studies by Noorwez and colleagues have demonstrated that retinoids and other related diffusible artificial chaperones can promote mutant rhodopsin binding of 11-cis-retinal such that it can function as a light chromophore (Noorwez et al. 2003, 2004, 2008). Mendes and colleagues have also recently demonstrated, in vitro, that retinoids and other agents that prevent protein aggregation can prevent cell death elicited by rhodopsin misfolding (Mendes and Cheetham 2008). These compounds suggest that preventing rhodopsin misfolding may be a new strategy to prevent retinal degeneration. This approach may also be efficacious in other retinal diseases arising from protein misfolding.

Acknowledgments We thank Victory Joseph for helpful comments. This work was funded by NIH grants EY01919, EY06842, EY02162, EY018313; the Foundation Fighting Blindness; and RPB.

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Chapter 15

Neural Retina and MerTK-Independent Apical

Polarity of αvβ5 Integrin Receptors in the

Retinal Pigment Epithelium

Mallika Mallavarapu and Silvia C. Finnemann

Abstract The apical plasma membrane domain of retinal pigment epithelial (RPE) cells in the eye faces the outer segment portions of rods and cones and the interphotoreceptor matrix in the subretinal space. Two important receptor-mediated interactions between the apical surface of the retinal pigment epithelium (RPE) and adjacent photoreceptors are adhesion ensuring outer segment alignment and diurnal phagocytosis of shed outer segment fragments contributing to outer segment renewal. Both depend on the apical distribution of the integrin family adhesion receptor αvβ5 as lack of αvβ5 in mice causes weakened retinal adhesion and asynchronous phagocytosis. With age, lack of αvβ5 leads to accumulation of harmful lipofuscin in the RPE and to vision loss. Here, we discuss three different possible mechanisms that could generate the exclusive apical distribution of αvβ5 integrin receptors in the RPE. (1) αvβ5 could be apical in the RPE because RPE attachment to neural retina generally or αvβ5 ligands specifically in the subretinal space stabilize apical but not basolateral αvβ5 surface receptors. (2) αvβ5 could be apical in the RPE because it resides in a complex with other components of the phagocytic machinery that assembles at the apical, phagocytic surface of the RPE. (3) αvβ5 could be apical due to mechanisms intrinsic to this receptor protein and specifically to its β5 integrin subunit.

Abbreviations

S.C. Finnemann (B)

Department of Biological Sciences, Fordham University, Bronx, NY 10458, USA e-mail: finnemann@fordham.edu

Medicine and Biology 664, DOI 10.1007/978-1-4419-1399-9_15,C Springer Science+Business Media, LLC 2010