Extrusion of lysosomal bodies from apical mouse retinal pigment epithelium

Mishima, Hiromu K.; Kondo, Kazuyoshi

doi:10.1007/bf00408162

Cited by 15 publications

(13 citation statements)

References 11 publications

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“…4B). This finding is in accord with observations of the RPE layer of younger wild-type animals (26).…”

Section: Ocular A2e and Atr-dimer-we Raised Two Groups Of Abca4supporting

confidence: 93%

“…The accumulation of lysosomal bodies in the control animals was most notable in the apical portions of the cytoplasm, a typical feature of the RPE of aged (24-month) wild-type mice (Fig. 4A) (26). On the other hand, only a few lysosomal bodies, sparsely distributed throughout the cytoplasm, were visible in the RPE of the treated animals (Fig.…”

Section: Ocular A2e and Atr-dimer-we Raised Two Groups Of Abca4mentioning

confidence: 85%

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C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

Kaufman

Zhang

et al. 2011

Journal of Biological Chemistry

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Autosomal recessive Stargardt disease (STGD1) is a macular dystrophy resulting from mutations in the ABCA4 (ABCR) gene. The age of onset of Stargardt disease is typically 10 -20 years of age and leads in almost all cases to blindness by age 50 (1, 2). A hallmark of the disease is premature lipofuscin accumulation in the retinal pigment epithelium (RPE) 2 of the eye. The RPE is critical for the neurosensory retina homeostasis; it acts as a transport exchange system with blood capillaries and is critical for regeneration and phagocytosis of photoreceptor outer segments. It is hypothesized that when RPE lipofuscin reaches a critical level, it contributes to a decline in cell function (3-8) resulting in the degeneration of the macular region of the neurosensory retina leading to loss of central vision (9 -11).The defective gene in Stargardt, ABCA4, encodes for an outer segment rim protein (RmP). The function of RmP is to transport the all-trans-retinaldehyde-phosphatidylethanolamine (retinaldehyde-PE) Schiff base from the luminal side of the disk membrane to the cytosolic face, where retinaldehyde can then be converted back to retinol (3). In the absence of its proper transporter, the retinaldehyde-PE conjugates may react to form vitamin A dimers (A2E and ATR-dimer among others), which are then deposited in the RPE after phagocytosis of the photoreceptors outer segments. Numerous studies have demonstrated the toxicity of vitamin A dimers to cultured RPE cells and they are hypothesized to play a key role in lipofuscin formation and subsequent retinal degeneration (12, 13). Nevertheless, the exact mechanisms that lead to lipofuscin accumulation or to vision loss as a result of the impaired transport of the retinaldehyde-PE conjugates remain unclear.In the accompanying article, we have shown that the ratedetermining step in vitamin A dimerization is the cleavage of a C20 carbon-hydrogen bond of the retinaldehyde-PE Schiff base (14). Replacing the C20 hydrogen atoms of vitamin A with deuterium atoms (i.e. C20-D 3 -vitamin A) makes this bond harder to cleave and impedes vitamin A dimerization (14). In this study we sought to determine whether retarding the intrinsic reactivity of vitamin A to dimerize could slow lipofuscin formation in the RPE and delay changes associated with human Stargardt disease. To accomplish this we raised ABCA4 Ϫ/Ϫ mutant albino mice (the mouse model of human Stargardt's disease) on diets containing either C20-D 3 -vitamin A (the treated group) or vitamin A at its natural isotopic abundance (the control group) and measured the concentration of vitamin A dimers, lipofuscin and other biological markers indicative of ocular health in both groups. Treated mice exhibited an 80% reduction in A2E, a 95% reduction in ATR dimer and a 70% decrease in fundus autofluorescence at three months of age. After six months, the treated group showed fewer lipofuscin granules as visualized qualitatively by electron microscopy, and at 12 months they showed improved eye function as measured by electroretinogram (ERG). ...

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“…4B). This finding is in accord with observations of the RPE layer of younger wild-type animals (26).…”

Section: Ocular A2e and Atr-dimer-we Raised Two Groups Of Abca4supporting

confidence: 93%

Section: Ocular A2e and Atr-dimer-we Raised Two Groups Of Abca4mentioning

confidence: 85%

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

Kaufman

Zhang

et al. 2011

Journal of Biological Chemistry

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“…13 Since aged mouse Bruch's membrane structures are not considered similar to human, the characteristic age changes of drusen formation, often seen in humans, are rarely seen in aged mouse Bruch's membrane. 20 However, an increase in size and number of lipofuscin granules are reported in the RPE. 21 Therefore, A2E measurement rather than identification of drusen should be the biomarker of mouse "AMD."…”

Section: Discussionmentioning

confidence: 99%

A High Omega-3 Fatty Acid Diet Reduces Retinal Lesions in a Murine Model of Macular Degeneration

Tuo

Ross

Herzlich

et al. 2009

The American Journal of Pathology

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Age-related macular degeneration (AMD) is one of the leading cause of blindness among the elderly; however, current therapy options are limited. Epidemiological studies have shown that a diet that is high in -3 polyunsaturated (n-3) fatty acids can slow disease progression in patients with advanced AMD. In this study, we evaluated the effect of such a diet on the retinas of Ccl2 ؊/؊ /Cx3cr1 ؊/؊ mice, a model that develops AMD-like retinal lesions that include focal deep retinal lesions, abnormal retinal pigment epithelium, photoreceptor degeneration, and A2E accumulation. Ccl2 ؊/؊ /Cx3cr1 ؊/؊ mice that ingested a high n-3 fatty acid diet showed a slower progression of retinal lesions compared with the low n-3 fatty acids group. Some mice that were given high levels of n-3 fatty acids had lesion reversion. We found a shunted arachidonic acid metabolism that resulted in decreased pro-inflammatory derivatives (prostaglandin E 2 and leukotriene B 4 ) and an increased antiinflammatory derivative (prostaglandin D 2 ). We also measured lower ocular TNF-␣ and IL-6 transcript levels in the mice fed a diet of high n-3 fatty acids. Our findings in these mice are in line with human studies of AMD risk reduction by long-chain n-3 fatty acids. This murine model provides a useful tool to evaluate therapies that might delay the development of AMD.

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“…Drusen formation in Bruch’s membrane has been hypothesized to come from RPE phagosomes via the basal pathway of secretion into Bruch’s membrane (Mishima and Hasebe, 1978). However, in mice, the accumulation of lysosomal bodies occurs apically in the RPE cytoplasm, causing dilation of RPE microvilli over time, and lysosomal bodies are extruded into the subretinal spaces to preserve RPE function (Mishima and Kondo, 1981). That is, mice do not have a tendency to accumulate lysosomes basally or secrete residual bodies into Bruch’s membrane like humans (Mishima and Kondo, 1981).…”

Section: The Use Of Murine Models For Amdmentioning

confidence: 99%

“…However, in mice, the accumulation of lysosomal bodies occurs apically in the RPE cytoplasm, causing dilation of RPE microvilli over time, and lysosomal bodies are extruded into the subretinal spaces to preserve RPE function (Mishima and Kondo, 1981). That is, mice do not have a tendency to accumulate lysosomes basally or secrete residual bodies into Bruch’s membrane like humans (Mishima and Kondo, 1981). For this reason, drusen and residual bodies in Bruch’s membrane are rarely seen in aged mice or transgenic mouse models.…”

Section: The Use Of Murine Models For Amdmentioning

confidence: 99%

Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)

Ramkumar

Zhang

Chan

2010

Progress in Retinal and Eye Research

131

123

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Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. The pathology of dry AMD consists of degeneration of photoreceptors and the RPE, lipofuscin (A2E) accumulation, and drusen formation. Mice have been widely used for generating models that simulate human AMD features for investigating the pathogenesis, treatment and prevention of the disease. Although the mouse has no macula, focal atrophy of photorecptors and RPE, lipofuscin accumulation, and increased A2E can develop in aged mouse eyes. However, drusen are rarely seen in mice because of their simpler Bruch's membrane and different process of lipofuscin extrusion compared with humans. Thus, analyzing basal deposits at the ultrastructural level and understanding the ultrastructural pathologic differences between various mouse AMD models are critical to comprehending the significance of research findings and response to possible therapeutic options for dry AMD.Based on the multifactorial pathogenesis of AMD, murine dry AMD models can be classified into three groups. First, genetically engineered mice that target genes related to juvenile macular dystrophies are the most common models, and they include abcr −/− (Stargardt disease), transgenic ELOVL4 (Stargardt-3 dominant inheritary disease), Efemp1 R345W/R345W (Doyne honeycomb retinal dystrophy), and Timp3 S156C/S156C (Sorsby fundus dystrophy) mice. Other murine models target genes relevant to AMD, including inflammatory genes such as Cfh −/− , Ccl2 −/− , Ccr2 −/− , Cx3cr1 −/− , and Ccl2 −/− /cx3cr1 −/− , oxidative stress associated genes such as Sod1 −/− and Sod2 knockdown, metabolic pathway genes such as neprilysin −/− (amyloid β), transgenic mcd/mcd (cathepsin D), Cp −/− /Heph −/Y (ferroxidase ceruloplasmin/hepaestin, iron metabolism), and transgenic ApoE4 on high fat and high cholesterol diet (lipid metabolism). Second, mice have also been immunologically manipulated by immunization with carboxyethylpyrrole (CEP), an oxidative fragment of DHA found in drusen, and found to present with dry AMD features. Third, natural mouse strains such as arrd2/arrd2 (Mdm gene mutation) and the senescence accelerated mice (SAM) spontaneously develop features of dry AMD like photoreceptor atrophy and thickening of Bruch's membrane.Corresponding author: Chi-Chao Chan, MD, 10 Center Drive, 10/10N103, NIH/NEI, Bethesda, MD 20892-1857. Tel: (301), 496-0417, Fax: (301) 402-8664, chanc@nei.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript Prog Retin Eye Res. Author ma...

show abstract

Extrusion of lysosomal bodies from apical mouse retinal pigment epithelium

Cited by 15 publications

References 11 publications

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

A High Omega-3 Fatty Acid Diet Reduces Retinal Lesions in a Murine Model of Macular Degeneration

Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)

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