Structural and molecular bases of rod photoreceptor morphogenesis and disease

Abstract

The rod cell has an extraordinarily specialized structure that allows it to carry out its unique function of detecting individual photons of light. Both the structural features of the rod and the metabolic processes required for highly amplified light detection seem to have rendered the rod especially sensitive to structural and metabolic defects, so that a large number of gene defects are primarily associated with rod cell death and give rise to blinding retinal dystrophies. The structures of the rod, especially those of the sensory cilium known as the outer segment, have been the subject of structural, biochemical, and genetic analysis for many years, but the molecular bases for rod morphogenesis and for cell death in rod dystrophies are still poorly understood. Recent developments in imaging technology, such as cryo-electron tomography and super-resolution fluorescence microscopy, in gene sequencing technology, and in gene editing technology are rapidly leading to new breakthroughs in our understanding of these questions. A summary is presented of our current understanding of selected aspects of these questions, highlighting areas of uncertainty and contention as well as recent discoveries that provide new insights. Examples of structural data from emerging imaging technologies are presented.

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration

“…1D), which represents an extended version of the transition zone found in all primary cilia (Anand and Khanna, 2012;Reiter et al, 2012). While primary cilia are slender organelles that protrude from the cell surface, connecting cilia provide a unique link between the cell body of the photoreceptor, where the entire protein synthesis machinery is localized, with the light-sensing outer segment, which is devoid of protein synthesis (Wensel et al, 2016). Considering the sheer size of the outer segment, it appears that among all different variants of cilia, the connecting cilia of photoreceptors might be the cilia with the single most solicited IFT machinery (Wright et al, 2010).…”

An inducible amphipathic helix within the intrinsically disordered C terminus can participate in membrane curvature generation by peripherin-2/rds

“…Maintaining this complex architecture represents a constant challenge for retinal photoreceptors, because a significant amount of disk membrane in each OS is renewed on a daily basis (3). The disruption of OS membrane structure or renewal by environmental and/or genetic causes compromises photoreceptor function and can lead to progressive and debilitating retinal diseases (4,5). An improved knowledge of normal OS structure is needed to advance understanding of how perturbations trigger pathogenic processes.…”

“…The molecular basis for the formation and maintenance of photoreceptor OS membrane architecture has begun to come into focus but is not yet well resolved (4,6). Advancing understanding in this area will require a molecular level knowledge of how individual OS disk structures are generated and maintained.…”

Large Animal Models of Inherited Retinal Degenerations: A Review

“…In the absence of the Pde6 holoenzyme, the cGMP hydrolyzing activity is absent and cGMP accumulates in the rod photoreceptors [41]. Increased cGMP is a well-established cause of photoreceptor cell death, likely due to the increased influx of calcium ions into the outer segment [42], triggering apoptosis [43]. The rod outer segments fail to mature in Pde6a −/− dogs and the genetically unaffected cones have stunted outer segments, which is reflected in a reduction in cone electroretinogram (ERG) a-waves early in the disease process [35].…”