Effect of Mutant Fibulin Expression on RPE Cell Function

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 segment 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.

Grantee institution at the time of this grant: Pennsylvania State University

A single genetic mutation in the fibulin-3 gene causes inherited early-onset macular degenerative diseases 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 the expression of a mutant protein might cause retinal pigment epithelial (RPE) cell dysfunction, leading to macular degeneration. Expression of fibulin-3 mutant protein leads to the accumulation of this protein in an intracellular organelle called the endoplasmic reticulum (ER), causing stress to this organelle.