ReviewAge-related macular degeneration: genetics and implications for detection and treatment
Age-related macular degeneration (ARMD) remains the most common cause of registerable blindness in the developed world. Despite extensive research, the pathogenesis of this condition remains elusive. Recent genetic advances in the understanding of inherited retinal dystrophies and the discovery of genes that code for retinal proteins have rekindled interest in the possibility of a genetic predisposition to ARMD. ARMD is most probably a disease with a multifactorial inheritance in which environmental factors can trigger disease in those who are ‘genetically primed’. If it were possible to detect predisposing genes in these people, then perhaps novel therapies or preventive measures could be directed towards those at risk in the pre-symptomatic stage, in the hope of either preventing disease or decreasing its severity.
References (0)
Cited by (18)
The role of inflammation in the pathogenesis of age-related macular degeneration
2006, Survey of OphthalmologyCitation Excerpt :By the year 2020, the number of individuals having AMD will increase by 50%.43 Although several lines of evidence, including twin and population-based aggregation studies63,79,80,100,117,133 have implicated a hereditary component in the disorder, other contributing factors such as diet, smoking, obesity, and underlying vascular disease may also be important.1,3,15,25,67,79,82,83,135,138,144,147,152 The association between cardiovascular disease and AMD is inferred from the histological similarity of atherosclerotic deposits within arterial vessels to those of drusen, the hallmark of AMD, in the eye.
Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is a complex disease to study because of the potential role of demographic, environmental, and other systemic risk factors, such as age, sex, race, light exposure, diet, smoking, and underlying cardiovascular disease which may contribute to the pathogenesis of this disease. Recently, single nucleotide polymorphisms, DNA sequence variations found within the complement Factor H gene, have been found to be strongly associated with the development of AMD in Caucasians. One single nucleotide polymorphism, Tyr402His, was associated with approximately 50% of AMD cases. We review recent developments in the molecular biology of AMD, including single nucleotide polymorphisms within the Factor H gene, which may predispose individuals to the susceptibility of AMD as well as single nucleotide polymorphisms that may confer a protective effect. Taken together these findings help to provide new insights into the central issues surrounding the pathogenesis of AMD.
Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration
2005, Progress in Retinal and Eye ResearchHuman retinal dystrophies and degenerations and light-induced retinal degenerations in animal models are sharing an important feature: visual cell death by apoptosis. Studying apoptosis may thus provide an important handle to understand mechanisms of cell death and to develop potential rescue strategies for blinding retinal diseases. Apoptosis is the regulated elimination of individual cells and constitutes an almost universal principle in developmental histogenesis and organogenesis and in the maintenance of tissue homeostasis in mature organs.
Here we present an overview on molecular and cellular mechanisms of apoptosis and summarize recent developments. The classical concept of apoptosis being initiated and executed by endopeptidases that cleave proteins at aspartate residues (Caspases) can no longer be held in its strict sense. There is an increasing number of caspase-independent pathways, involving apoptosis inducing factor, endonuclease G, poly-(ADP-ribose) polymerase-1, proteasomes, lysosomes and others. Similarly, a considerable number and diversity of pro-apoptotic stimuli is being explored.
We focus on apoptosis pathways in our model: light-damage induced by short exposures to bright white light and highlight those essential conditions known so far in the apoptotic death cascade. In our model, the visual pigment rhodopsin is the essential mediator of the initial death signal. The rate of rhodopsin regeneration defines damage threshold in different strains of mice. This rate depends on the level of the pigment epithelial protein RPE65, which in turn depends on the amino acid (leucine or methionine) encoded at position 450. Activation of the pro-apoptotic transcription factor AP-1 constitutes an essential death signal. Inhibition of rhodopsin regeneration as well as suppression of AP-1 confers complete protection in our system.
Furthermore, we describe observations in other light-damage systems as well as characteristics of animal models for RP with particular emphasis on rescue strategies. There is a vast array of different neuroprotective cytokines that are applied in light-damage and RP animal models and show diverging efficacy. Some cytokines protect against light damage as well as against RP in animal models. At present, the mechanisms of neuroprotective/anti-apoptotic action represent a “black box” which needs to be explored.
Even though acute light damage and RP animal models show different characteristics in many respects, we hope to gain insights into apoptotic mechanisms for both conditions by studying light damage and comparing results with those obtained in animal models.
In our view, future directions may include the investigation of different apoptotic pathways in light damage (and inherited animal models). Emphasis should also be placed on mechanisms of removal of dead cells in apoptosis, which appears to be more important than initially recognized. In this context, a stimulating concept concerns age-related macular degeneration, where an insufficiency of macrophages removing debris that results from cell death and photoreceptor turnover might be an important pathogenetic event. In acute light damage, the appearance of macrophages as well as phagocytosis by the retinal pigment epithelium are a consistent and conspicuous feature, which lends itself to the study of removal of cellular debris in apoptosis.
We are aware of the many excellent reviews and the earlier work paving the way to our current knowledge and understanding of retinal degeneration, photoreceptor apoptosis and neuroprotection. However, we limited this review mainly to work published in the last 7–8 years and we apologize to all the researchers which have contributed to the field but are not cited here.
Defective cone photoreceptor cytoskeleton, alignment, feedback, and energetics can lead to energy depletion in macular degeneration
2004, Progress in Retinal and Eye ResearchMacular degeneration (MD) is a puzzling disease characterized by disturbance, and then complete loss, of fine detailed vision in the central macular region of the human retina, as a result of disturbed function and then death of photoreceptor cells. This review describes a possible pathomechanism for MD that involves a causal relationship between mutated genes, altered photoreceptor cytoskeletal proteins, defective cone photoreceptor alignment, and disturbed visual feedback mechanisms that leads to energy depletion and apoptosis of macular cone photoreceptors.
MD may be associated with mutations in genes encoding certain photoreceptor proteins (ATP-binding cassette transporter retina, retinitis pigmentosa GTPase regulator, retinal degeneration slow/peripherin) that are components of, or interact with, microtubule-containing cytoskeletal systems at the connecting cilium of rods and cones and at the multiple incisures of rod outer segments (OSs).
Vertebrate photoreceptors are directionally sensitive: the longitudinal axis of each cell is actively aligned towards the entrance pupil of the eye, and the cells are most sensitive to light travelling along this axis (as in the Stiles–Crawford effect). The mechanisms responsible for photoreceptor alignment involve movements made by photoreceptors in response to the direction of incident light, using their cytoskeletons. A model is proposed for photoreceptor alignment whereby light absorption in the OS causes fast membrane and slower cytoplasmic changes that spread from the OS to the inner segment myoid, where they activate feedback-controlled motor functions by cytoskeletal elements (microtubules and microfilaments) to produce a differential local bending that adjusts photoreceptor orientation.
The fovea at the center of the human macula has specialized features that enable it to provide uniquely high visual acuity, if its cones are accurately aligned. Accordingly, it is proposed that some gene defects in MD cause disturbances at photoreceptor connecting cilia that lead to gradual defects in photoreceptor alignment; misalignment of central macular cones will be initially perceived as blurring, distortions, and decreased acuity of central vision.
Although photoreceptors throughout the retina use their cytoskeletons for alignment, the accurate alignment of foveal cones is particularly important because their signals contain fine resolution information that is used in visual feedback systems, e.g., for adjusting accommodation and eye movements. Vision involves multiple feedback loops that are interdependent, e.g., the accuracy of alignment of foveal cones influences how effectively changes in accommodation bring images into focus, and the state of accommodation in turn influences how light entering the eye is projected onto foveal cones.
It is proposed that in MD gene defects that disturb the cytoskeleton and alignment of photoreceptors lead to a disturbance in the normal signalling within these feedback systems, causing the mechanisms controlling the alignment of cones in the center of the macula to become progressively more disturbed and the cells to unnecessarily expend energy. These disturbances can lead to local energy depletion within the metabolically fragile central macular cones that trigger them to die, producing central areas of blindness. If this line of reasoning is correct, it may be possible to treat the local energy depletion within macular cones in MD by energy supplementation.
Genetic factors of age-related macular degeneration
2004, Progress in Retinal and Eye ResearchAge-related macular degeneration (AMD) is a leading cause of blindness in the United States and developed countries. Although the etiology and pathogenesis of AMD remain unknown, a complex interaction of genetic and environmental factors is thought to exist. The incidence and progression of all of the features of AMD are known to increase significantly with age. The tendency for familial aggregation and the findings of gene variation association studies implicate a significant genetic component in the development of AMD. This review summarizes in detail the AMD-related genes identified by studies on genetically engineered and spontaneously gene-mutated (naturally mutated) animals, AMD chromosomal loci identified by linkage studies, AMD-related genes identified through studies of monogenic degenerative retinal diseases, and AMD-related gene variation identified by association studies.
Age-related macular degeneration: The lipofuscin component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells
2000, Journal of Biological Chemistry10–20% of individuals over the age of 65 suffer from age-related macular degeneration (AMD), the leading cause of severe visual impairment in humans living in developed countries. The pathogenesis of this complex disease is poorly understood, and no efficient therapy or prevention exists to date. A precondition for AMD appears to be the accumulation of the age pigment lipofuscin in lysosomes of retinal pigment epithelial (RPE) cells. In AMD, these cells seem to die by apoptosis with subsequent death of photoreceptor cells, and light may accelerate the disease process. Intracellular factors leading to cell death are not known. Here we show that the lipophilic cation N-retinyl-N-retinylidene ethanolamine (A2E), a lipofuscin component, induces apoptosis in RPE and other cells at concentrations found in human retina. Apoptosis is accompanied by the appearance of the proapoptotic proteins cytochromec and apoptosis-inducing factor in the cytoplasm and the nucleus. Biochemical examinations show that A2E specifically targets cytochrome oxidase (COX). With both isolated mitochondria and purified COX, A2E inhibits oxygen consumption synergistically with light. Inhibition is reversed by the addition of cytochrome c or cardiolipin, a negatively charged phospholipid that facilitates the binding of cytochrome c to membranes. Succinate dehydrogenase activity is not altered by A2E. We suggest that A2E can act as a proapoptotic molecule via a mitochondria-related mechanism, possibly through site-specific targeting of this cation to COX. Loss of RPE cell viability through inhibition of mitochondrial function might constitute a pivotal step toward the progressive degeneration of the central retina.
Epidemiological profile of age-related macular degeneration patients in Federal University of Parana, Brazil
2016, Revista Brasileira de Oftalmologia
- 1
Tel:+44 1232 240503 ext. 3152 Fax:+44 1232 330744.