Lytic photoreceptor cell death caused by Rab escort protein deficiency in Drosophila.

Abstract

Choroideremia (CHM) is a rare X-linked recessive form of inherited retinal degeneration caused by the deficiency of the Rab escort protein 1 (REP1)-encoding CHM gene. REP1 is essential for the post-translational prenylation of the key players in intracellular membrane trafficking, the Rab GTPases. In this study, we aimed to analyze the mechanisms of retinal degeneration caused by Rep deficiency using the Drosophila retina as a model system. Rab GTPases lost their membrane association ability and diffused into the cytoplasm, and the accumulation of unprenylated Rab6 and Rab7 was observed in Rep-deficient photoreceptors. Notably, Rep-deficient photoreceptors underwent progressive cell death via cell swelling and rupture rather than apoptosis. These findings provide new insight to seek a therapeutic approach to CHM. Impact statement Choroideremia is an inherited retinal degeneration caused by a deficiency of Rab escort protein 1 (Rep-1). We used the Drosophila retina as a model to study the mechanism of retinal degeneration in Rep-deficiency and found that Rep-deficient photoreceptors undergo progressive cell death via cell swelling and rupture rather than apoptosis.