Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors

Recent data have provided important clues about the molecular mechanisms underlying certain retinal degenerative diseases, including retinitis pigmentosa and age-related macular degeneration. Photoreceptor cell degeneration is a feature common to these diseases, and the death of these cells in many instances seems to involve the closely associated retinal pigment epithelial (RPE) cells. Under normal circumstances, both cell types are subject to potentially damaging stimuli (e.g. sunlight and high oxygen tension). However, the mechanism or mechanisms by which homeostasis is maintained in this part of the eye, which is crucial for sight, are an unsolved riddle. The omega-3 fatty acid family member docosahexaenoic acid (DHA), which is enriched in these cells, is the precursor of neuroprotectin D1 (NPD1). NPD1 inhibits oxidative-stress-mediated proinflammatory gene induction and apoptosis, and consequently promotes RPE cell survival. This enhanced understanding of the molecular basis of endogenous anti-inflammatory and neuroprotective signaling in the RPE presents an opportunity for the development of therapies for retinal degenerative diseases.

Introduction

Photoreceptor cells (rods and cones) are specialized neurons (Figure 1a), and their damage and apoptotic death are hallmarks of retinal degenerative diseases 1, 2, 3. In retinitis pigmentosa (RP; a heterogeneous group of inherited blinding diseases), death of rod photoreceptors initially occurs in the periphery of the retina, whereas in age-related macular degeneration (AMD; the leading cause of loss of sight in those over the age of 65), progressive perturbation and loss of visual acuity are due to photoreceptor death in the center of the retina, the macula [4]. It is becoming evident that in retinal degeneration there are diverse triggers of photoreceptor cell death. Integral to this demise is the close relationship between photoreceptors and another key cell type, the retinal pigment epithelial (RPE) cells (Figure 1a,c). In Stargardt's disease (a juvenile form of AMD), and in other retinal degeneration in which RPE cell functional integrity is initially compromised, photoreceptors are damaged. Moreover, if RPE cells die, the photoreceptor cells then succumb [5]. Our understanding of these diseases is further complicated by >150 mutations of photoreceptor-specific proteins that have been reported to contribute to RP, including mutations of rhodopsin, peripherin, the β subunit of cGMP phosphodiesterase, and retinal outer-segment membrane protein 1 (ROM1) 6, 7. In autosomal-dominant RP, the genes involved include some that are expressed in the choriocapillaris [8]. AMD, by contrast, is a complex group of disorders with multifactorial causes, both genetic and environmental; the main known risk factor is advanced age. Moreover, the choriocapillaris and the stratified extracellular matrix (Bruch's membrane), which separates the RPE from the choriocapillaris, are also affected in AMD [9]. Initiation and progression of this retinal degeneration involves an unsuccessful inflammatory response. Very recent findings that support this possibility have identified variants (single nucleotide polymorphisms) in the genes encoding factor H (CFH/HF1) [10], factor B (BF) and complement component 2 (C2) [11] as major risk factors for AMD. Factor H is an inhibitor of the alternative pathway of complement system activation that, as result, has the property of limiting cell injury and inflammation [12].

Complex intracellular and intercellular signaling events that are, at present, incompletely understood are set into motion in the initial stages of retinal degeneration. Overall, oxidative and nitrosative stress are enhanced and exaggerated, usually at abnormal cellular locations and with inappropriate timing. Mitochondrial function is compromised, and this dysfunction is central in these impairments 8, 13, 14.

Because the early clinical manifestations of most retinal degeneration precedes massive photoreceptor cell death, it is important to define the initial crucial events. This knowledge might be applicable to the design of novel therapeutic interventions to halt or slow disease progression. Among these early events, RPE cells might respond through the generation of counteracting cell-protective anti-inflammatory, pro-survival repair signals, including the induction of anti-apoptotic proteins and/or inhibition of pro-apoptotic proteins. This review summarizes the recent identification of an endogenous mediator of RPE cell survival, namely the docosahexaenoic acid (DHA) derivative neuroprotectin D1 (NPD1), and its implications for retinal degenerative diseases.