Control of protein and lipid composition of photoreceptor outer segments-Implications for retinal disease.

Vision is arguably our most important sense, and its loss brings substantial limitations to daily life for affected individuals. Light is perceived in retinal photoreceptors (PRs), which are highly specialized neurons subdivided into several compartments with distinct functions. The outer segments (OSs) of photoreceptors represent highly specialized primary ciliary compartments hosting the phototransduction cascade, which transforms incoming light into a neuronal signal. Retinal disease can result from various pathomechanisms originating in distinct subcompartments of the PR cell, or in the retinal pigment epithelium which supports the PRs. Dysfunction of primary cilia causes human disorders known as "ciliopathies", in which retinal disease is a common feature. This chapter focuses on PR OSs, discussing the mechanisms controlling their complex structure and composition. A sequence of tightly regulated sorting and trafficking events, both upstream of and within this ciliary compartment, ensures the establishment and maintenance of the adequate proteome and lipidome required for signaling in response to light. We discuss in particular our current understanding of the role of ciliopathy proteins involved in multi-protein complexes at the ciliary transition zone (CC2D2A) or BBSome (BBS1) and how their dysfunction causes retinal disease. While the loss of CC2D2A prevents the fusion of vesicles and delivery of the photopigment rhodopsin to the ciliary base, leading to early OS ultrastructural defects, BBS1 deficiency results in precocious accumulation of cholesterol in mutant OSs and decreased visual function preceding morphological changes. These distinct pathomechanisms underscore the central role of ciliary proteins involved in multiple processes controlling OS protein and lipid composition.