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PubMed1991

Interactions of nucleotide analogues with rod outer segment guanylate cyclase.

Light activation of cyclic GMP hydrolysis in rod outer segments is mediated by a G-protein which is active in the GTP-bound form. Substitution of GTP with a nonhydrolyzable GTP analogue is thought to leave the G-protein in a persistently activated state, thereby prolonging the hydrolysis of cyclic GMP. Restoration of cyclic GMP concentration in the cell also depends upon GTP since it is the substrate for guanylate cyclase, but little is known about the effects of GTP analogues on this enzyme. We report here the effects of the analogues of GTP and ATP as inhibitors and substrates of rod disk membrane guanylate cyclase. The rate of cyclic GMP synthesis from GTP in rod disk membranes was about 50 pmol min-1 (nmol of rhodopsin)-1. Analogues of GTP and adenine nucleotides competitively inhibited the cyclase activity. The order of inhibition, with magnesium as metal cofactor, was ATP greater than GMP-PNP greater than AMP-PNP approximately GTP-gamma-S; with manganese, AMP-PNP was more inhibitory than GTP-gamma-S. The inhibition constants, with magnesium as cofactor, were 0.65-2.0 mM for GTP-gamma-S, 0.4-0.8 mM for GMP-PNP, 1.5-2.3 mM for AMP-PNP, and 0.07-0.2 mM for ATP. The fraction of cyclase activity inhibited by analogues was similar at 1 and 0.03 microM calcium. Besides inhibition of cyclase, the analogues also served as its substrates. GTP-gamma-S substituted GTP with about 85% efficiency while GMP-PNP and ATP were about 5 and 7% as efficient, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Properties of base-substituted and carboxyl-esterified analogues of griseolic acid, a potent cAMP phosphodiesterase inhibitor.

Griseolic acid (GA) is a potent cyclic AMP (cAMP) phosphodiesterase (PDE) inhibitor that has an adenine base and two carboxyl groups in its molecule (Nakagawa F, Okazaki T, Naito A, Iijima Y and Yamazaki M, J Antibiot 38: 823-829, 1985). GA analogues were synthesized in which the adenine group was substituted with guanine (6-deamino-2-amino-6-hydroxygriseolic acid, G-GA) or hypoxanthine (6-deamino-6-hydroxygriseolic acid, H-GA). Their inhibitory activities to cyclic GMP (cGMP) PDE and cAMP PDE were compared with GA. For cGMP PDE from rod outer segments of bovine retina, the IC50 values of GA, G-GA and H-GA were 18, 0.040 and 0.12 microM, respectively, with 0.25 microM cGMP as substrate. For type IV PDE isozyme from mouse 3T3 fibroblast cells, the IC50 values of GA, G-GA and H-GA were 0.021, 15 and 11 microM, respectively, with 0.25 microM cAMP as substrate. Thus, GA and G-GA were found to be base-selective inhibitors of type IV PDE of 3T3 cells and type V PDE of bovine retinas, respectively. Esters of carboxylic acids of GA were synthesized in order to increase permeability into cells, and their efficacy was tested by measuring the accumulation of cAMP in 3T3 cells. The dipivaloyloxymethyl ester of GA was found to increase cAMP levels at 0.1 microM, while GA and 3-isobutyl-1-methylxanthine were active only above 100 microM, and the dimethyl ester of GA was inactive. The dipivaloyloxymethyl ester of GA seems to exert its activity after conversion to GA in the cell, since the pivaloyloxymethyl ester was easily hydrolysed by the enzyme action and the dipivaloyloxymethyl ester of GA itself was much less potent an inhibitor of PDE. The dipivaloyloxymethyl ester of GA inhibited thrombin-induced aggregation of platelets and stimulated lipolysis of adipocytes at low concentrations.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Cytodifferentiation of photoreceptors in larval goldfish: delayed maturation of rods.

This study describes the differentiation of photoreceptors in larval goldfish retina. The earliest photoreceptors to differentiate were cones; 3H-fucose labeled cone but not rod outer segments in larval as well as adult goldfish. All major cone types known to be present in the adult goldfish retina (double cones, long and short single cones) were found in the larval retina by 2 days after hatching. The cones matured rapidly; within a few days they had well-developed outer segments and synaptic pedicles that were smaller, but otherwise similar to those in adults. Rods were slower to mature. Their outer segments were at first short, wide, and misshapen; only as they grew longer and narrower did they become straight and properly aligned. Rod spherules were first seen in fish older than 1 month; immature rods contained perinuclear synaptic ribbons and invaginating processes penetrated the cell body. These results suggest that the influence of rods and cones on visual function in larval goldfish may be quite different from the adult.

Animals↗
PubMed1994

Early morphometry of a retinal dystrophy in Labrador retrievers.

Retinal morphometry was assessed in 7 dogs from a colony of Labrador Retrievers with dystrophic retinas at 1,2,3,4 and 18 months of age. Rod outer segment length and outer nuclear layer width were measured in the central, midperipheral and peripheral retina at six locations along the vertical meridian. Early striking regional differences in onset and rate of progression were characteristic for this inherited retinal degeneration. Notably, some areas of the retina developed fully and normally before degenerating. The central parts of the vertical meridians showed slightly disorganized rod outer segments already at 1 month of age and they were significantly shorter than those of control animals at 3 and 4 months (p < 0.01 and p < 0.001, respectively). The rod outer segments of the midperipheral and peripheral regions were, however, comparable to control animals as late as at 4 months of age. At 18 months the rod outer segments of dystrophic animals were significantly shorter in all retinal regions (p < 0.0005). At the age the outer nuclear layer of the dystrophic animals had become significantly thinner than that of control animals in all retinal regions (p < 0.001), indicating a clear visual cell loss. It is reasonable to characterize this as a retinal degeneration having a relatively slow progression, which enhances its relevance to conditions of clinical significance.

Aging↗
PubMed1985

Studies on hereditary retinal degeneration. The rd gene in the mouse.

Stearic, oleic, linoleic, arachidonic, and docosahexaenoic acids can be detected regularly in the eyes and retinae of mice. During the period of maturation of the outer segments of the rod, the amount of each fatty acid increases, the most striking feature of which is the accumulation of docosahexaenoic acid in the retina, which might reflect the growth of rod outer segments. In rd/rd mice, fatty acid synthesis is reduced and the change characteristic of docosahexaenoic acid is absent. Analysis of the structure of outer segment disc membranes by the freeze fracturing technique, however, shows that the structure of the membrane is probably not affected by the rd gene.

Animals↗
PubMed1980

Two components of electrical dark noise in toad retinal rod outer segments.

1. Physiological noise in the visual transduction mechanism was studied by recording membrane current from single rod outer segments in pieces of isolated toad retina. 2. The inward current in darkness showed spontaneous fluctuations which disappeared during the response to bright light. 3. The dark noise consisted of two components, a continuous fluctuation of rms amplitude about 0.2 pA and occasional discrete events about 1 pA in size. 4. Intervals between discrete events followed the exponential distribution expected of a Poisson process with a mean rate of about one event per 50 sec (20 degrees C). 5. The amplitude and power spectrum of the discrete events resembled those of single photon effects in the same rod, suggesting that discrete events may arise from spontaneous activation of single rhodopsin molecules. 6. The temperature dependence of the mean frequency of occurrence of discrete events gave an activation energy of 22 kcal mole-1, probably characteristic of thermal isomerization of rhodopsin. 7. The variance of the continuous component of the dark noise rose linearly with the length of the outer segment drawn into the suction electrode, indicating that this component is generated in the outer segment. 8. The power spectrum of a rod's continuous noise was usually fitted by the square of a Lorentzian with the same time constant as that of the four first-order delays in the cell's single photon response. The shot effects composing the continuous component thus appear to be shaped by two of four sequential processes in transduction. 9. The variance and spectrum of the continuous noise are interpreted to reflect shot effects about 1/400 the size of a single photon effect occurring at a frequency of 6 x 10(3) sec-1. 10. The rod's flash sensitivity was halved by a steady light to giving about 8 photoisomerizations sec-1. The much lower mean rate of discrete events indicates that Io in increment sensitivity experiments on individual receptors is not set by thermal activation of rhodopsin. 11. Values of sensitivity and time-to-peak flash response collected from many cells in darkness were correlated by the same power law relation obtaining in the presence of backgrounds. The correlation observed would be explained if a single variable controlled both the gain and time scale of several stages of the transduction mechanism in background light and in darkness.

Animals↗
PubMed1996

Photoreceptor repair in response to RPE transplants in RCS rats: outer segment regeneration.

PURPOSE: We have previously shown that transplants of normal rat neonatal RPE cells rescued photoreceptor cells in retinas of Royal College of Surgeons (RCS) dystrophic rats for up to one year. In this study, we investigated the photoreceptor rescue effects in RCS rats within the first three weeks following transplantation in an attempt to determine if RPE transplants initiate repair mechanisms, specifically, outer segment (OS) regeneration. METHODS: Freshly isolated RPE cells from neonatal pigmented Long Evans rats were transplanted into the subretinal space of 22-23 day-old RCS rats using a transscleral approach. For controls, vehicle was similarly injected. RESULTS: When analyzed at 10 days post-transplantation, long inner segments were observed with short buds of outer segment growth in the area of the RPE-cell transplants. The outer segments were of insufficient length to be measured at 10 days, but by 14 and 21 days, OS were 2.02 +/- 0.32 microns and 18.80 +/- 2.78 microns, respectively. In vehicle-injected retinas from 10 to 21 days postsurgery, outer segments were not observed and the inner segments were three-fold shorter than in RPE-transplanted retinas. At 10 days post-transplantation, most RPE cells were seen in the subretinal space, but a few had attached to Bruch's membrane; however, by 21 days, many of the transplanted RPE cells had attached to Bruch's membrane, although a few were found free in the subretinal space. CONCLUSIONS: This study has shown that transplants of normal rat neonatal RPE cells have the capacity to support not only photoreceptor cell survival but also initiate early repair mechanisms as exhibited by outer segment regeneration in RCS retinas. These results also conclusively show the important role that the RPE plays in outer segment growth and maturation.

Animals↗
PubMed1985

Photoreceptor GTP binding protein mediates fluoride activation of phosphodiesterase.

In this report, we show that fluoride activates dark-adapted rod outer segment phosphodiesterase, and that this activation is mediated, in analogy with adenylate cyclase, through a GTP binding protein. The GTP binding protein is released from dark-adapted rod outer segment membranes by exposure to fluoride and subsequent centrifugation. The 39-kilodalton subunit of the GTP binding protein, released from the membrane by this procedure, exhibits altered susceptibility to limited trypsin proteolysis, identical to that seen when hydrolysis-resistant GTP analogs are bound to that subunit. Repeated exposure of dark-adapted rod outer segment membranes to fluoride and subsequent centrifugation results in maximal activation of the membrane-bound phosphodiesterase. Thus, activation of phosphodiesterase by fluoride in the dark appears similar to fluoride activation of adenylate cyclase.

Animals↗
PubMedDate not supplied

[Outer segments of the retinal photoreceptors of vertebrates: the ultrastructure, development and renewal of the disks].

The external photoreceptor segments in the retina of vertebrates have been studied already more than 100 years; the intensity of these studies increased markedly during the recent 20 years due to the introduction of autoradiography and electron microscopy. These methods allowed to study the ultrastructure of external segments of the rods and cones in many vertebrate species, its development in ontogenesis, the renewal of external segments and the dependence of renewal on the diurnal rhythm of illumination. All these data have never been summed up and discussed. This review provides a general picture of studies of different aspects of the ultrastructure of external segments; the models of formation of the external segments' discs proposed by several authors are considered; the necessity of continuation and widening of comparative studies of the ultrastructure of external photoreceptor segments in different vertebrates is founded. The most important conclusions concern the differences between the rods and the cones during renewal of the membranes discs of external segments.

Animals↗
PubMed1982

Serum antibody responses to bovine retinal S-antigen and rod outer segments in proliferative diabetic retinopathy before and after argon laser photocoagulation.

Using the enzyme-linked immunosorbent assay, the serum antibody titers to bovine retinal S-antigen and rod outer segments in pre- and post-argon laser treated diabetic retinopathy patients were compared to each other and to the titers of age- and sex-matched normal controls. The increase in anti-S titer following the initial laser treatment gave a P less than 0.01 using the two-tailed paired Student's t-analysis as compared to the prelaser anti-S titer. Both pre- and post-laser anti-S titers were elevated over normal controls with P values of less than 0.02 and less than 0.001, respectively. Eight weeks after the initial laser treatment, anti-S titers began to decline approaching control levels 12 weeks later. No significant change was found between pre- and post-laser titers when rod outer segments were used as antigen although the pre- and post-laser titers were increased over normal controls with P values of less than 0.05 and less than 0.001, respectively. The release and possible alteration of retinal components following photocoagulation may account for the rise in anti-S titers, while the prephotocoagulation titers may be due to retinopathy-related photoreceptor cell alteration.

Adult↗
PubMed1983

ATP causes a structural change in retinal rod outer segments: disc swelling is not involved.

Mg2+-ATP was found to produce a 15 to 30% drop in the turbidity of suspensions of broken retinal rod outer segments from the toad Bufo marinus, prepared by washing or flotation in sucrose. This in vitro process has a half-time of about two minutes and appears to be irreversible. It is not affected by the bleaching of rhodopsin. Direct measurements show that the drop in turbidity is not due to swelling of the disc internal space measured in outer segments recovered by centrifugation. Instead, the total packed volume of the outer segments increases following incubation in Mg2+-ATP. Under the specific conditions of these experiments, the total pellet volume increase was 26 +/- 22% (13 experiments) when corrected for the percent of rhodopsin recovered in the centrifugal pellet. The magnitude of the ATP effect on turbidity suggests that the majority of the discs are involved in some kind of structural change. Vanadium in the +5 oxidation state (vanadate) is an inhibitor of the Mg2+-ATP effect on turbidity at a half-maximal concentration of 0.2 to 0.4 microM, and inhibition is rapidly reversed by norepinephrine, which complexes vanadate. A Mg2+-ATPase activity in extensively washed outer segment membranes, previously shown to be activated as much as twofold following light exposure of the membranes, is not sensitive to vanadate at the concentrations which block the ATP-dependent change of turbidity.

Adenosine Triphosphate↗
PubMed1995

Inhibition of rhodopsin kinase by recoverin. Further evidence for a negative feedback system in phototransduction.

Recoverin is a 23-kDa Ca(2+)-binding protein found predominantly in vertebrate photoreceptor cells. Recent electrophysiological and biochemical studies suggest that recoverin may regulate the photoresponse by inhibiting rhodopsin phosphorylation. We find in both cell homogenates and reconstituted systems that the inhibition of rhodopsin phosphorylation by recoverin occurs over a significantly higher free Ca2+ range than previously reported. Half-maximal inhibition occurs at 1.5-3 microM free Ca2+ and is cooperative with a Hill coefficient of approximately 2. Measurements of transducin activation demonstrate that this inhibition prolongs the lifetime of catalytically active rhodopsin. Ca(2+)-recoverin directly inhibits rhodopsin kinase activity, and Ca(2+)-dependent binding of recoverin to rod outer segment membranes is not required for its action. Extrapolation of the in vitro data to in vivo conditions based on simple mass action calculations places the Ca(2+)-recoverin regulation within the physiological free Ca2+ range in intact rod outer segment. The data are consistent with a model in which the fall in free Ca2+ that accompanies rod excitation exerts negative feedback by relieving inhibition of rhodopsin phosphorylation.

Animals↗
PubMedDate not supplied

Nitric oxide synthesis in retinal photoreceptor cells.

Nitric oxide (NO) is known to be synthesized in several tissues and to increase the formation of cyclic GMP through the activation of soluble guanylate cyclases. Since cyclic GMP plays an important role in visual transduction, we investigated the presence of nitric oxide synthesizing activity in retinal rod outer segments. Bovine rod outer segments were isolated intact and separated into membrane and cytosolic fractions. Nitric oxide synthase activity was assayed by measuring the conversion of L-arginine to L-citrulline. Both membrane and cytosolic fractions were active in the presence of calcium and calmodulin. The activity in both fractions was stimulated by the nitric oxide synthase cofactors FAD, FMN, and tetrahydrobiopterin and inhibited by the L-arginine analog, L-monomethyl arginine. The Km for L-arginine was similar, about 5 microM for the enzyme in both fractions. However, the two fractions differed in their calcium/calmodulin dependence: the membrane fraction exhibited basal activity even in the absence of added calcium and calmodulin while the cytosolic fraction was inactive. But the activity increased in both fractions when supplemented with calcium/calmodulin: in membranes from about 40 to 110 fmol/min/mg of protein and in the cytosol from near zero to about 350 fmol/min/mg of protein in assays carried out at 0.3 microM L-arginine. The two enzymes also responded differently to detergent: the activity of the membrane enzyme was doubled by Triton X-100 while that of the cytosolic enzyme was unaffected. These results show that NO is produced by cytosolic and membrane-associated enzymes with distinguishable properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1992

Studies on the interaction of alpha subunits of GTP-binding proteins with beta gamma dimers.

The interaction of several preparations of purified beta gamma dimers with two types of guanosine-nucleotide-binding-regulatory-(G)-protein alpha subunits, a recombinant bv alpha i3, made in Sf9 Spodoptera frugiperda cells by the baculovirus (bv) expression system, and alpha s, either purified from human erythrocyte Gs-type GTP-binding protein, and activated by NaF/AlCl3, or unpurified as found in a natural membrane, were studied. The beta gamma dimers used were from bovine rod outer segments (ROS), bovine brain, human erythrocytes (hRBC) and human placenta and contained distinct ratios of beta subunits that, upon electrophoresis, migrated as two bands with approximate M(r) of 35,000 and 36,000, as well as distinct complements of at least two gamma subunits each. When tested for their ability to recombine at submaximal concentrations with bv alpha i3, ROS, brain, hRBC and placental beta gamma dimers exhibited apparent affinities that were the same within a factor of two. When bovine brain, placental and ROS beta gamma dimers were tested for their ability to promote deactivation of Gs, brain and placental beta gamma dimers were equipotent and at least 10-fold more potent than that of ROS beta gamma dimers; likewise, brain beta gamma and placental dimers were equipotent in inhibiting GTP-activated and GTP-plus-isoproterenol-activated adenylyl cyclase, while ROS beta gamma dimers were less potent when assayed at the same concentration. The possibility that different alpha subunits may distinguish subsets of beta gamma dimers from a single cell was investigated by analyzing the beta gamma composition of three G proteins, Gs, Gi2 and Gi3, purified to near homogeneity from a single cell type, the human erythrocyte. No evidence for an alpha-subunit-specific difference in beta gamma composition was found. These findings suggests that, in most cells, alpha subunits interact indistinctly with a common pool of beta gamma dimers. However, since at least one beta gamma preparation (ROS) showed unique behavior, it is clear that there may be mechanisms by which some combinations of beta gamma dimers may exhibit selectivity for the alpha subunits they interact with.

Adenosine Diphosphate Ribose↗
PubMed2000

Dietary 20:4n-6 and 22:6n-3 modulates the profile of long- and very-long-chain fatty acids, rhodopsin content, and kinetics in developing photoreceptor cells.

The objective of this study was to determine whether addition of dietary 20:4n-6 and 22:6n-3 to a conventional infant formula fat blend influences membrane long-chain and very-long-chain fatty acid composition, rhodopsin content, and rhodopsin kinetics in developing rat photoreceptor cells. The dietary fats were formulated based on the fat composition of a conventional infant formula providing an 18:2n-6/18:3n-3 ratio of 7:1 (SMA, Wyeth Nutritionals), which served as the control fat blend. This dietary fat blend was modified to contain 20:4n-6 [arachidonic acid (AA)], 22:6n-3 [docosahexaenoic acid (DHA)], AA + DHA, or an 18:2n-6/18:3n-3 ratio of 4:1 (alpha-linolenic acid). Dams were fed diets from birth, and rat pups were fed the same diet after weaning. Retinas and rod outer segments were prepared in the dark from pups at 2, 3, and 6 wk of age for fatty acid analysis of individual phospholipids, rhodopsin content, and rhodopsin disappearance kinetics after light exposure. Feeding AA + DHA in the diet increased 22:6n-3 levels in phosphatidylcholine and phosphatidylethanolamine. In phosphatidylcholine, total n-6 tetraenoic very-long-chain fatty acids and total n-3 pentaenoic and n-3 hexaenoic very-long-chain fatty acids increased after feeding AA and DHA, respectively. Developmental changes were characterized by a decrease in 20:4n-6 in the major phospholipids, whereas 22:6n-3 increased with age in rod outer segments. The highest rhodopsin content occurred in the retina of rats fed diets containing AA and/or DHA. The kinetics of rhodopsin disappearance after light exposure was highest in rats fed DHA at 6 wk of age. This study demonstrates that small manipulations of the dietary level of 20:4n-6 and 22:6n-3 are important determinants of fatty acid composition of membrane lipid and visual pigment content and kinetics in the developing photoreceptor cell.

Animals↗
PubMed1993

A comparison of phagocytosis by the retinal pigment epithelium in normal and delayed amelanotic chickens.

The retinal pigment epithelium (RPE) performs a critical role in maintaining the integrity and renewal of the retinal system by clearing the shed photoreceptor outer segment debris through the process of phagocytosis. If phagocytosis is impaired, accumulation of the debris occurs leading to the degeneration of the retina. Phagocytosis, measured by polyvinyl toluene bead uptake is a normal cell activity exhibited by the embryonic retinal pigment epithelium even before complete differentiation of the neuronal layers. It is significant that embryonic pigment epithelium from either normal or delayed amelanotic (DAM) strain is competent in the process of non-specific particle uptake. In normal chickens non-specific phagocytic activity is observable as early as embryonic day 9 and continues through the rest of the developmental period and throughout adult life. The retinal pigment epithelium in DAM chickens exhibits early phagocytic activity at embryonic day 9 and then through day 16, but by day 19 this function is lost. This loss of phagocytic capacity in RPE of the DAM strain precedes and may be instrumental in the gradual retinal degeneration exhibited by these animals. Specific phagocytosis of rod outer segments (ROS) was examined in 4-week-old post-hatch normal and DAM RPE. Phagocytosis of ROS was greatly reduced in DAM RPE implying that the defect in the DAM is expressed in non-specific and specific phagocytosis. This study indicates that the DAM retinal system can now serve as an alternative and comparative model for studying different aspects of retinal degeneration.

Animals↗
PubMed1989

Lipofuscin-like substances accumulate rapidly in brain, retina and internal organs with cysteine protease inhibition.

The protease inhibitor, leupeptin, has been previously shown to cause an accumulation of lysosomally associated intracytoplasmic dense bodies resembling lipofuscin when administered intraventricularly to the brains of young rats (Ivy et al., Science, 226:985, 1984). These findings support the idea that lipofuscin formation during normal aging involves perturbed proteolytic degradation. In the current study, we delineate more precisely the proteolytic mechanisms in question and examine the effects of protease inhibition on other tissues and species. Four sets of experiments were done. In the first, rats were administered leupeptin (L; an inhibitor of cysteine and some serine proteases), E-64C (a cysteine protease inhibitor), chloroquine (C; a lysosomal enzyme inhibitor), aprotinin (A; a serine protease inhibitor) or physiological saline (S) into the lateral ventricle of the brain at a constant rate for two weeks using an osmotic mini-pump. In the second set, beagle dogs were administered L or S intraventricularly in a similar fashion. In the third set, young rats received intraocular injections of L, E64C, C, A or S from 1 to 9 days at 24 hr intervals. In the fourth set, young rats and mice were administered L, E-64C or S intraperitoneally via an osmotic mini-pump for 2 or more weeks. The tissue of all animals was processed for light and electron microscopy as well as for fluorescence analysis. In rat brain cells (especially hippocampus and cerebellum), substances which by morphological, histochemical and fluorescence emission criteria resemble lipofuscin, accumulated following L, C or E64C, but not A or S treatment. A similar buildup of lipofuscin-like substance occurred in canine brain following L but not S infusion. In retinal pigment epithelial cells, undigested rod outer segment discs accumulated after L, C or E-64C and possibly A, but not after S injections. With increasing survival times, the accumulated substances became morphologically more similar to lipofuscin. Cells of liver (both hepatocytes and non-parenchymal cells) and kidney (mainly renal tubule cells) also accumulated substances resembling lipofuscin in response to L but not S infusion; other internal organs were differentially affected. These results demonstrate 1) that specific inhibition of cysteine proteases is sufficient to cause accumulation of lipofuscin-like substances in brain and retina and 2) that several species and organ systems are similarly affected by protease inhibition. Taken together, these findings are consistent with the idea that defective or decreased proteolysis by lysosomal cysteine proteases is responsible for lipofuscin accumulation during normal aging.

Aging↗
PubMed1995

Ultrastructural features of retinal dystrophy in mutant vitiligo mice.

Ultrastructural features of the retinal pigment epithelium and photoreceptor cells were studied in vitiligo (C57BL/6 mivit/mivit) mice. Eyes from 12-day- to 56-week-old animals were analysed. Abnormal photoreceptors were seen in 12-day-old mice. By 3 weeks malformed outer segments were evident in the posterior and equatorial retina, but normal photoreceptors were present in the periphery. By 28 weeks, a marked gradient in cell loss was evident, with a progressive increase in cell viability along the posterior-peripheral axis. Viable intact photoreceptors were still present in the peripheral retina of 56-week-old mice. Melanosome content varied between adjacent pigment epithelium cells in both the posterior and peripheral retina. In the choroid, however, a steep posterior-peripheral gradient in melanosome content was evident with highest pigmentation in the periphery. In the optic nerve head region abnormal development of photoreceptors was correlated with proliferation of abnormal pigment epithelium cells. Accumulation of rod outer segment debris in the posterior and peripheral subretinal space preceded photoreceptor cell death. Short pigment epithelial microvilli without proper attachment to photoreceptors are suggestive of alterations in pigment-epithelium-photoreceptor interaction, which might affect photoreceptor differentiation and phagocytosis of rod outer segments by pigment epithelium cells.

Animals↗