Aberrant protein trafficking in retinal degenerations: The initial phase of retinal remodeling

Abstract

Retinal trafficking proteins are involved in molecular assemblies that govern protein transport, orchestrate cellular events involved in cilia formation, regulate signal transduction, autophagy and endocytic trafficking, all of which if not properly controlled initiate retinal degeneration. Improper function and or trafficking of these proteins and molecular networks they are involved in cause a detrimental cascade of neural retinal remodeling due to cell death, resulting as devastating blinding diseases. A universal finding in retinal degenerative diseases is the profound detection of retinal remodeling, occurring as a phased modification of neural retinal function and structure, which begins at the molecular level. Retinal remodeling instigated by aberrant trafficking of proteins encompasses many forms of retinal degenerations, such as the diverse forms of retinitis pigmentosa (RP) and disorders that resemble RP through mutations in the rhodopsin gene, retinal ciliopathies, and some forms of glaucoma and age-related macular degeneration (AMD). As a large majority of genes associated with these different retinopathies are overlapping, it is imperative to understand their underlying molecular mechanisms. This review will discuss some of the most recent discoveries in vertebrate retinal remodeling and retinal degenerations caused by protein mistrafficking.

Keywords: Glaucoma; Protein trafficking; Retinal remodeling; Retinitis pigmentosa; Rhodopsin; Transition zone cilia.

Figure 1

The vertebrate retina and rod cell highlighting trafficking proteins. Scanning electron micrograph (SEM) of wild-type mouse reveals the precise architecture of the neural retina (left). Schematic of rod cell (middle) highlighting an outer (OS), connecting cilium (CC) and inner segment (IS). Retinal pigmented epithelial (RPE) cells lay over the photoreceptor OS. Schematic of transition zone, BBSome and trans-Golgi network showing the hypothesized order and localization of the trafficking proteins (right) discussed in this review and others. SEM taken by Alecia K. Gross and Ivan Anastassov at the Marine Biological Labs, Fundamental Issues in Vision Research course 2010. *, tips of rod OS.

Figure 2

Retinal remodeling at 10 day and 4 week-old hrhoG/hrhoG mice. Electron micrographs of ultrathin retinal sections comparing wild-type (+/+), (A and B), heterozygote (+/hrhoG), (C and D) and homozygous knock-in mice (hrhoG/hrhoG), (E and F), knock-in mice generated by segmental replacement (hrhoG(H)/hrhoG(H)), (G and H) and homozygous rhodopsin knockout mice (−/−), (I and J). Astericks (*) indicate visible connecting cilia (A, C, E, and G), whereas diamonds indicate nascent disk stacks in +/+ and +/hrhoG mice (A and C). Evident disorganized lamellae are present in hrhoG/hrhoG mice by 4 weeks. Pigment granules in the RPE are the darken patches in hrhoG(H)/hrhoG(H) and −/− mice (G and I). Reprinted from Vision Research, Volume 46, Issue 27, Alecia K. Gross, Glenn Decker, Fung Chan, Ivette M. Sandoval, John H. Wilson, Theodore G. Wensel, ‘Defective development of photoreceptor membranes in a mouse model of recessive retinal degeneration’ 4510–4518, Copyright (2006) with permission from Elsevier.