Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

Abstract

Photoreceptors undergo a constant renewal of their light sensitive outer segments (POSs). In the renewal process, 10% of the POS mass is daily phagocytized by the adjacent retinal pigment epithelium (RPE). POS contain vast amounts of 11-cis retinal and alltrans-retinal, two highly reactive vitamin A aldehydes that spontaneously dimerize into lipid bisretinoids (LBs) and accumulate into RPE lysosomes during phagocytosis. As LBs are refractory to lysosomal hydrolases and RPE cells do not divide, this accumulation is irreversible and results in the formation of lipofuscin granules. Lipofuscin accumulation is toxic for RPE cells through a variety of light-dependent and light-independent mechanisms. Beyond a threshold, RPE cells die resulting in secondary loss of overlying photoreceptors. Currently, there are no efective treatments for retinal disorders associated with genetic or age-associated LB accumulation, such as Stargardt disease and age-related macular degeneration (AMD). Thus, there is a great need for medical interventions. Here, we discuss the current understanding of lipofuscin's pathogenicity and the status of diferent strategies under development to promote LB elimination from RPE lysosomes.Keywords: lipofuscin, Stargardt, age-related macular degeneration (AMD), bisretinoids, retinal pigment epithelium (RPE), cyclodextrins, cellular clearance, TFEB, lysosome IntroductionTo understand the origin and consequences of the lysosomal accumulation of lipofuscin in the eye, a basic knowledge of retinal function and organization is required.© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The retinal pigment epithelium (RPE) in vertebrate's eyesLight entering the eye gets refracted by the cornea and lens on the neural retina, where photoreceptors (PR) convert photons into a cascade of chemical and electrical events that propagate to second-order (horizontal, bipolar, and amacrine cells) and third-order (ganglion cells) retinal neurons, which distribute this information to various visual centers of the brain through the ibers of the optic nerve. The bodies of PR cells, rods and cones, display three sectors (Figure 1): the outer segment, illed with stacks of disks densely packed with light-sensitive photopigment; the inner segment, illed with genetic, biosynthetic, and metabolic organelles Lysosomes -Associated Diseases and Methods to Study Their Function 4(nucleus, endoplasmic reticulum, Golgi complex, ribosomes, mitochondria); and the synaptic terminal that connects with bipolar neurons of the retina. In vertebrates, the retina is inverted in the sense that light passes through secondary and tertiary neuronal layers in the inner retina before reaching the rods and cones in the outer retina (Figure 1). Photoreceptors are metabolically very active cells that req...

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“…Excessive oxidation also induces the formation of lipofuscin in the RPE, which is an undegradable complex of intracellular protein aggregation [71]. The accumulation of lipofuscin can lead to cellular toxicity and functional impairment of RPE cells, which may be involved in AMD development [72].…”

Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue

“…We, therefore, hypothesized that there could be colocalization between glucosepane and lipofuscin, a lysosomally derived, non-degradable, heterogeneous molecular aggregate that is partially characterized by its granular appearance. Previous reports have proposed that the accumulation of lipofuscin within the RPE is considered to be a risk factor for age-related diseases of the eye . Lipofuscin has been shown to induce lysosomal dysfunction and interfere with autophagic clearance, contributing to the development of various eye pathologies, including AMD. − There is also evidence that AGEs promote formation of lipofuscin and that AGE-modified proteins may be components of lipofuscin granules. , …”

“…Previous reports have proposed that the accumulation of lipofuscin within the RPE is considered to be a risk factor for age-related diseases of the eye. 35 Lipofuscin has been shown to induce lysosomal dysfunction and interfere with autophagic clearance, contributing to the development of various eye pathologies, including AMD. 36−39 There is also evidence that AGEs promote formation of lipofuscin and that AGE-modified proteins may be components of lipofuscin granules.…”

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“…In these cells, oxidative stress inactivates the proteasome, promoting ER stress, and seems to be one of the mechanisms to explain the accumulation of ubiquitin conjugates upon oxidative stress [ 84 ]. Proteasomal inhibition can also increase lipofuscin formation [ 85 ], a hallmark of AMD pathogenesis [ 86 ]. Proteasomal over-inhibition results in the expression of hypoxia-inducible factor (HIF)-1α and NF-kappaB, factors that regulate the expression and secretion of proangiogenic factors such as VEGF [ 87 ].…”