Effect of Mutant Fibulin Expression on RPE Cell Function

Project Summary

A single genetic mutation in the fibulin-3 gene causes inherited early-onset macular degenerative disease known as Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD). Similar mutations in other fibulins (5 and 6) are linked to age-related macular degeneration (AMD). These mutations cause the expression of abnormal forms of fibulin proteins. How these abnormal proteins contribute to macular degeneration is unknown. We provide a testable hypothesis of how expression of a mutant protein might cause retinal pigment epithelial (RPE) cell dysfunction leading to macular degeneration. Expression of fibulin-3 mutant protein lead to accumulation of this protein in an intracellular organelle called the endoplasmic reticulum (ER), causing stress to this organelle. We hypothesize that the expression of mutant fibulin proteins compromises the ability of RPE cells to perform one of their primary functions, swallowing and processing of outer segments that are shed from photoreceptor cells. Evidence suggests that the rate of outer segments shedding and the ability of the RPE to remove and process the outer segments are key factors in the progression of AMD. The proposed studies would expand our understanding of these vital RPE functions, and could point the way to AMD treatments that act by alleviating protein aggregation.