Accumulation Of Lipofuscin In Retinal Pigment Epithelium Research Articles

Two distinct phenotypes in pigmented cells of different embryonic origins in eyes of pale ear mice

The eye has pigmented cells of two different embryonic origins and therefore it is a good model for studying melanosome biogenesis and melanin production/deposition. Pale ear mice bear a mutation in the Hermansky–Pudlak syndrome type 1 (HPS-1) gene and exhibit abnormal eye pigmentation. Here, we reported the delayed and reduced pigmentation in eyes of pale ear mice in early postnatal stages and adulthood. Tyrosinase assay and l-3,4-dihydroxyphenylalanine (l-DOPA) gel staining assay revealed that tyrosinase activity in eyes of pale ear mutants was greatly reduced in early postnatal stages and increased gradually after postnatal day 7 (P7). Further histological examination revealed that hypopigmentation in the retinal pigment epithelium (RPE) and pigment epithelium of the iris and ciliary body, which are derived from the optic cup, was more severe than that in neural crest-derived tissues. In addition, macromelanosomes were exclusively present in neural crest-derived melanocytes of pale ear adults, but absent at early postnatal stages. Taken together, the mutation in the HPS-1 gene could cause two distinct phenotypes in pigmented cells of different embryonic origins. Besides, an increased accumulation of lipofuscin in RPE was also observed.

Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy

Leber congenital amaurosis (LCA), a severe autosomal recessive childhood blindness, is caused by mutations in at least 15 genes. The most common molecular form is a ciliopathy due to NPHP6 (CEP290) mutations and subjects have profound loss of vision. A similarly severe phenotype occurs in the related ciliopathy NPHP5 (IQCB1)-LCA. Recent success of retinal gene therapy in one form of LCA prompted the question whether we know enough about human NPHP5 and NPHP6 disease to plan such treatment. We determined that there was early-onset rapid degeneration of rod photoreceptors in young subjects with these ciliopathies. Rod outer segment (OS) lamination, when detectable, was disorganized. Retinal pigment epithelium lipofuscin accumulation indicated that rods had existed in the past in most subjects. In contrast to early rod losses, the all-cone human fovea in NPHP5- and NPHP6-LCA of all ages retained cone nuclei, albeit with abnormal inner segments and OS. The rd16 mouse, carrying a hypomorphic Nphp6 allele, was a good model of the rod-dominant human extra-foveal retina. Rd16 mice showed normal genesis of photoreceptors, including the formation of cilia, followed by abnormal elaboration of OS and rapid degeneration. To produce a model of the all-cone human fovea in NPHP6-LCA, we generated rd16;Nrl-/- double-mutant mice. They showed substantially retained cone photoreceptors with disproportionate cone function loss, such as in the human disease. NPHP5- and NPHP6-LCA across a wide age spectrum are thus excellent candidates for cone-directed gene augmentation therapy, and the rd16;Nrl-/- mouse is an appropriate model for pre-clinical proof-of-concept studies.

Neuro‐retinal disorders in Trf2 mutant zebrafish

By applying ionizing irradiation (IR+) on wild‐type (WT), and Trf2 mutant (both homo and heterozygous mutant) backgrounds, we observed the neurodegenerative phenotypes and neuro‐retinal disorders in the adult zebrafish and their offspring. The offspring from irradiated parental fish revealed several malformations in eyes during early development, suggesting that the integrity of the gametogenic processes is compromised beyond generations. We have identified abnormal neuro‐retinal development in the homozygous Trf2 mutant embryos that also accelerated retinal aging symptoms in adult heterozygous Trf2 mutant fish. The partial loss‐of‐function (decrease‐of‐function) of telomeric protein TRF2 is responsible for late‐onset retinal disorders as well as neuro‐retinal development with losing genomic integrity. A functional link and crosstalk between p53 and TRF2 in neuro‐retinal development has been demonstrated in both embryonic neuro‐retinal development and adult retinal function in zebrafish. The genetic effects of TRF2 and p53 insufficiency in neuro‐retinal systems of IR+ adults and their offspring detected. In the adult Trf2 mutant fish, we observed the development of AMD (age‐related macular degenerative disease)‐like symptoms with retinal dysfunctions. In our preliminary results, adult heterozygous Trf2 mutant fish showed accumulations of autofluorescent drusen‐like material around the retinal pigment epithelium (RPE) in their earlier age than that of WT siblings. The age‐related macular degeneration caused by the accumulation of lipofuscin in RPE revealed in the retinae of Trf2 mutant zebrafish. These studies exposed a new insight into retinal disorders in Vertebrates and established zebrafish as an efficient model organism for studying human retinal abnormalities and stress‐associated neural disease researches.

Potential role of retinal pigment epithelial lipofuscin accumulation in age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of severe visual impairment in developed countries. The vision loss associated with AMD is the result of degenerative changes in the central region of the retina called the macula. Maintenance of normal structure and function of the macular retina, and of the remainder of the retina as well, is critically dependent on the supporting role of the adjacent retinal pigment epithelium (RPE). Impairment of normal RPE functions is known to result in retinal degeneration and loss of visual function. Thus, it has been hypothesized that the retinal degeneration that characterizes AMD is secondary to age-related deterioration in RPE support functions. Like many other postmitotic cell types, the RPE accumulates autofluorescent lysosomal storage bodies (lipofuscin) during senescence. In human eyes, lipofuscin comes to occupy a substantial fraction of the RPE cytoplasmic volume in the elderly. Does this lipofuscin accumulation contribute to the development of AMD? This question is a specific case of the broader question of whether lipofuscin accumulation in general is detrimental to cells. Unfortunately, definitive data do not exist to allow these questions to be answered. Although a correlation between RPE lipofuscin content and AMD has been reported, a cause-and-effect relationship between RPE lipofuscin accumulation and the development of this disease has not been established. It has been reported that a mutation in a gene encoding a photoreceptor-specific protein results in massive RPE lipofuscin accumulation and early-onset macular degeneration. However, again the accelerated RPE lipofuscin accumulation has not been shown to be the cause of the accompanying macular degeneration. The lack of a definitive link between RPE lipofuscin accumulation and AMD illustrates one of the biggest challenges remaining in lipofuscin research—determining whether lipofuscin accumulation per se has an impact on cell function.

Total Synthesis of the Ocular Age Pigment A2-E: A Convergent Pathway

Total Synthesis of the Ocular Age Pigment A2-E: A Convergent Pathway

Lipofuscin autofluorescence: Evidence for vitamin A involvement in the retina

A lipofuscin-like autofluorescence develops in the degenerating photoreceptor cells of the RCS rat, a strain with inherited retinal dystrophy. In animals with normal retinas, age-related lipofuscin accumulation in the eye is restricted to the retinal pigment epithelium (RPE). Previous investigations have established that RPE lipofuscin accumulation in the normal rat retina can be reduced by dietary vitamin A deficiency. In order to determine whether the photoreceptor-derived fluorescence in the RCS rat retina is related to RPE lipofuscin fluorescence, the influence of dietary vitamin A on the fluorophore content of the RCS rat retina was studied. Vitamin A deficiency substantially reduced the autofluorescence associated with degenerating photoreceptor cells of the RCS rat retina. A specific vitamin A-dependent fluorophore was isolated from these retinas using thin-layer chromatography (TLC). The mobility of this fluorophore on TLC differs from that of the major age-dependent fluorophore isolated from the RPE of normal rats. Thus, if the vitamin A-dependent fluorophores of the photoreceptors and RPE are related, it appears that the fluorophore generated in the photoreceptor cells must undergo chemical modification once it has been taken up by the RPE. The fact that both the RPE- and photoreceptor-associated fluorophores are vitamin A-dependent suggests that such a relationship between them is likely. These experiments indicate that the RPE is somewhat different from other lipofuscin-accumulating tissues in that a major precursor of RPE lipofuscin fluorophores originates in another cell type and enters the RPE via phagocytosis.