Mitochondrial DNA Polymorphism A4917G Is Independently Associated with Age-Related Macular Degeneration

Canter, Jeffrey A.; Olson, Lana M.; Spencer, Kylee L.; Schnetz-Boutaud, Nathalie; Anderson, Brent; Hauser, Michael A.; Schmidt, Silke; Postel, Eric A.; Agarwal, Anita; Pericak‐Vance, Margaret A.; Sternberg, Paul; Haines, Jonathan L.

doi:10.1371/journal.pone.0002091

Cited by 99 publications

(72 citation statements)

References 21 publications

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“…Other risk factors like obesity and atherosclerotic vascular disease have less consistent fi ndings and weaker associations, and no association exists between ARMD and diabetes or ARMD and plasma cholesterol levels. Linkage studies and genomewide scans have identifi ed polymorphisms in complement factors H and I, HTRA1, ARMS2, and mitochondrial DNA polymorphism A4917G as risk factors, and complement factor B, C3, and apolipoprotein (apo)E4 as protective factors (32)(33)(34)(35)(36)(37)(38)(39).…”

Section: Epidemiology and Risk Factorsmentioning

confidence: 99%

Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration

Curcio

Johnson

Huang

et al. 2010

Journal of Lipid Research

166

145

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Section: Epidemiology and Risk Factorsmentioning

confidence: 99%

Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration

Curcio

Johnson

Huang

et al. 2010

Journal of Lipid Research

166

145

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“…mtDNA isolated from macular RPE of individuals with AMD exhibits significantly more damage than that from age-matched controls (19). Genetic studies implicate several mtDNA haplotypes (20,21) and a nuclear gene encoding a mitochondria-associated protein (22) as AMD risk factors. Moreover, the RPE appears to be the initial site of pathogenesis in retinopathies associated with inherited mtDNA mutations (23), which can preferentially affect the macula (24,25).…”

Section: Introductionmentioning

confidence: 99%

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Zhao

Yasumura²,

Li³

et al. 2011

J. Clin. Invest.

272

309

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Retinal pigment epithelial (RPE) cell dysfunction plays a central role in various retinal degenerative diseases, but knowledge is limited regarding the pathways responsible for adult RPE stress responses in vivo. RPE mitochondrial dysfunction has been implicated in the pathogenesis of several forms of retinal degeneration. Here we have shown that postnatal ablation of RPE mitochondrial oxidative phosphorylation in mice triggers gradual epithelium dedifferentiation, typified by reduction of RPE-characteristic proteins and cellular hypertrophy. The electrical response of the retina to light decreased and photoreceptors eventually degenerated. Abnormal RPE cell behavior was associated with increased glycolysis and activation of, and dependence upon, the hepatocyte growth factor/met proto-oncogene pathway. RPE dedifferentiation and hypertrophy arose through stimulation of the AKT/mammalian target of rapamycin (AKT/mTOR) pathway. Administration of an oxidant to wild-type mice also caused RPE dedifferentiation and mTOR activation. Importantly, treatment with the mTOR inhibitor rapamycin blunted key aspects of dedifferentiation and preserved photoreceptor function for both insults. These results reveal an in vivo response of the mature RPE to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function. Our findings provide a rationale for mTOR pathway inhibition as a therapeutic strategy for retinal degenerative diseases involving RPE stress. IntroductionThe retinal pigment epithelium (RPE) is a polarized, cuboidal epithelial cell layer situated in the outer retina between the photoreceptors and choroidal vasculature. The RPE supplies an estimated 60% of the glucose consumed by the neural retina (1) and performs a variety of other functions crucial for retinal homeostasis, including delivery of amino acids and docosahexaenoic acid for photoreceptor protein and membrane synthesis; transport, storage, and enzymatic conversion of retinoids essential for phototransduction; regulation of fluid and ion balance in the subretinal space; maintenance of the blood retinal barrier; secretion of growth factors; and phagocytosis of shed photoreceptor outer segment membranes (2). The RPE is a postmitotic tissue, so RPE cells must carry out these functions for the life of an individual.The retinal degenerative consequences of mutations in RPEexpressed genes illustrate the importance of the RPE for photoreceptor viability in humans. Mutations that impair production of the chromophore 11-cis retinal cause Leber congenital amaurosis, retinitis pigmentosa (RP), and allied disorders (3). Disruption of RPE phagocytosis causes RP and rod/cone dystrophy (4, 5). Mutations that affect ion channel function cause disease of the specialized retinal region necessary for high-acuity vision (the macula) (6) as well as RP (7), while mutations in genes encoding the RPE-secreted proteins TIMP3 (8) and EFEMP1 (9) cause lateronset macular disease.

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“…It has emerged over the last 5 or so years that major pathological features involving sub-retinal drusen deposition and choroidal neovascularization that are associated with one form of multifactorial retinopathy, namely age-related macular degeneration, where the central cone-rich part of the retina, or macula, degenerates, can now be explained, at least in part, by excessive complement activity on ocular surfaces. [24][25][26][27][28][29][30] However, the influence of complement on cone photoreceptor survival is less clear in hereditary (as opposed to multi-factorial) forms of retinal disease. Here we show that levels of C1q, the primary component of the classical complement pathway, rise substantially in retinal tissues over the course of degeneration in mice induced by a targeted disruption of the rhodopsin gene, a model of autosomal recessive RP and that in the absence of C1q (RhoÀ/ ÀC1qaÀ/À) cone photoreceptor function and viability are significantly compromised.…”

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confidence: 99%

C1q enhances cone photoreceptor survival in a mouse model of autosomal recessive retinitis pigmentosa

et al. 2011

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Retinitis pigmentosa (RP) is a degenerative retinal disease involving progressive loss of rod and cone photoreceptor function. It represents the most common form of registered blindness among the working aged populations of developed countries. Given the immense genetic heterogeneity associated with this disease, parameters influencing cone photoreceptor survival (preservation of daytime vision) that are independent of primary mutations are exceedingly important to identify from a therapeutic standpoint. Here we identify C1q, the primary component of the classical complement pathway, as a cone photoreceptor neuronal survival factor. European Journal of Human Genetics (2012) 20, 64-68; doi:10.1038/ejhg.2011; published online 24 August 2011Keywords: C1qa; C3; retinopathy; retinitis pigmentosa; complement; cone photoreceptors INTRODUCTION Hereditary retinopathies, prominent among which is retinitis pigmentosa (RP), conditions involving progressive death of photoreceptors are amongst the most genetically heterogeneous of any group of mendelian conditions. Including Leber's congenital amaurosis (LCA), a congenital retinopathy with pathological features bearing similarities to RP, 60 genes have now been implicated in disease etiology. If syndromic forms of disease and other hereditary retinopathies are included, 202 genetic loci have been identified and a total of 161 genes so far characterized. 1 RP segregates largely in an autosomal dominant, recessive, or X-linked recessive manner, 2 whereas all of the 16 genetic forms of LCA that have been identified to date are autosomal recessive; hence, gene therapies require strategies based either on gene replacement, or on the selective suppression of dominantly mutated genes, or their transcripts. Progress is being made to the extent that clinical trials involving AAV-mediated gene replacement have now been established for one form of LCA caused by mutations within the RPE65 gene. [3][4][5] In addition, therapeutic modalities have been demonstrated for other genetic subtypes of RP and LCA in a growing number of animal models, both of recessive and dominant forms of disease. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Notwithstanding such progress, the genetic complexity of this group of diseases represents a formidable logistic and economic hurdle in developing viable methods of prevention. Given this caveat, parameters effecting photoreceptor survival that are independent of the primary genetic lesion are critically important to identify. It has emerged over the last 5 or so years that major pathological features involving sub-retinal drusen deposition and choroidal neovascularization that are associated with one form of multifactorial retinopathy, namely age-related macular degeneration, where the central cone-rich part of the retina, or macula, degenerates, can now be explained, at least in part, by excessive complement activity on ocular surfaces. [24][25][26][27][28][29][30] However, the influence of complement on cone photoreceptor survival is...

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Mitochondrial DNA Polymorphism A4917G Is Independently Associated with Age-Related Macular Degeneration

Cited by 99 publications

References 21 publications

Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration

Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

C1q enhances cone photoreceptor survival in a mouse model of autosomal recessive retinitis pigmentosa

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