Complement Factor H Deficiency Results in Decreased Neuroretinal Expression of<i>Cd59a</i>in Aged Mice

Faber, Carsten; Williams, Jennifer A. E.; Juel, Helene Bæk; Greenwood, John; Nissen, Mogens Holst; Moss, Stephen E.

doi:10.1167/iovs.12-10385

Cited by 19 publications

(24 citation statements)

References 35 publications

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“…The requirement for protection against complement activation clearly exists in the retina since rod and cone photoreceptors in human eyes, and astroglial cells in mouse eyes have been shown to express DAF [6, 7], and we also reported that CD59a and CFH are up-regulated in the mouse neuroretina in normal ageing, again supporting the idea that complement regulation is required for maintenance of a healthy retina [8]. …”

Section: Introductionsupporting

confidence: 75%

Exposure to the complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis

Shi

Williams²,

Guo³

et al. 2015

Apoptosis

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The loss of photoreceptors is the defining characteristic of many retinal degenerative diseases, but the mechanisms that regulate photoreceptor cell death are not fully understood. Here we have used the 661W cone photoreceptor cell line to ask whether exposure to the terminal complement complex C5b-9 induces cell death and/or modulates the sensitivity of these cells to other cellular stressors. 661W cone photoreceptors were exposed to complete normal human serum following antibody blockade of CD59. Apoptosis induction was assessed morphologically, by flow cytometry, and on western blotting by probing for cleaved PARP and activated caspase-3. Necroptosis was assessed by flow cytometry and Sirtuin 2 inhibition using 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furyl]-N-5-quinolinylacrylamide (AGK2). The sensitivity of 661W cells to ionomycin, staurosporine, peroxide and chelerythrine was also investigated, with or without prior formation of C5b-9. 661W cells underwent apoptotic cell death following exposure to C5b-9, as judged by poly(ADP-ribose) polymerase 1 cleavage and activation of caspase-3. We also observed apoptotic cell death in response to staurosporine, but 661W cells were resistant to both ionomycin and peroxide. Interestingly, C5b-9 significantly increased 661W sensitivity to staurosporine-induced apoptosis and necroptosis. These studies show that low levels of C5b-9 on 661W cells can induce apoptosis, and that C5b-9 specifically sensitizes 661W cells to certain apoptotic and necroptotic pathways. Our observations provide new insight into the potential role of the complement system in photoreceptor loss, with implications for the molecular aetiology of retinal disease.

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Section: Introductionsupporting

confidence: 75%

Exposure to the complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis

Shi

Williams²,

Guo³

et al. 2015

Apoptosis

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“…We also showed that FADS1 expression is significantly increased in RPE-choroid, but not neuroretina, of young Cfh null mice, an early-stage AMD model [21]. FADS1 and FADS2 encode delta-5 and delta-6 desaturases, respectively, which are membrane-bound enzymes that catalyze the formation of long-chain polyunsaturated fatty acids such as DHA and eicosapentaenoic acid (EPA) [43].…”

Section: Discussionmentioning

confidence: 94%

Potential protective function of the sterol regulatory element binding factor 1–fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration

Ashikawa

Nishimura

Okabe

et al. 2017

Heliyon

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Age-related macular degeneration (AMD) is the most common cause of vision loss in elderly individuals throughout the developed world. Inhibitors of vascular endothelial growth factor have been successfully used to treat choroidal neovascularization in late-stage AMD. The pathogenesis of early-stage AMD, however, remains largely unknown, impairing efforts to develop effective therapies that prevent progression to late-stage AMD. To address this, we performed comparative transcriptomics of macular and extramacular retinal pigmented epithelium-choroid (RPE-choroid) tissue from early-stage AMD patients. We found that expression of fatty acid desaturase 1 (FADS1), FADS2, and acetyl-CoA acetyltransferase 2 (ACAT2) is increased in macular but not extramacular tissue, possibly through activation of sterol regulatory element binding factor 1 (SREBF1). Consistent with this, we also found that expression of Fads1 is increased in RPE-choroid in a mouse model of early-stage AMD. In zebrafish, deletion of fads2, which encodes a protein that functions as both Fads1 and Fads2 in other species, enhanced apoptosis in the retina upon exposure to intense light. Similarly, pharmacological inhibition of Srebf1 enhanced apoptosis and reduced fads2 expression in zebrafish exposed to intense light. These results suggest that the SREBF1–FADS1/2 axis may be activated in macular RPE-choroid as a protective response during early-stage AMD and could thus be a therapeutic target for early-stage AMD.

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“…In two-year old Cfh −/− mice, we observed a number of abnormalities including reduced visual acuity and loss of rod function, and structural changes to the photoreceptors and Bruch’s membrane but it is not known when these functional and anatomical abnormalities begin in Cfh −/− mice. In a separate study we performed a microarray analysis of neural retina and retinal pigment epithelium (RPE) from these mice to investigate the consequences of Cfh deletion on age-related changes in gene expression, and observed anomalies in the expression patterns of certain complement regulators as a function of age [12].…”

Section: Introductionmentioning

confidence: 99%

Retinal Changes Precede Visual Dysfunction in the Complement Factor H Knockout Mouse

Williams¹,

Greenwood²,

Moss³

2013

PLoS ONE

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We previously reported that aged mice lacking complement factor H (CFH) exhibit visual defects and structural changes in the retina. However, it is not known whether this phenotype is age-related or is the consequence of disturbed development. To address this question we investigated the effect of Cfh gene deletion on the retinal phenotype of young and mid-age mice. Cfh −/− mouse eyes exhibited thickening of the retina and reduced nuclear density, but relatively normal scotopic and photopic electroretinograms. At 12 months there was evidence of subtle astroglial activation in the Cfh −/− eyes, and significant elevation of the complement regulator, decay-accelerating factor (DAF) in Müller cells. In the retinal pigment epithelium (RPE) of young control and Cfh −/− animals mitochondria and melanosomes were oriented basally and apically respectively, whereas the apical positioning of melanosomes was significantly perturbed in the mid-age Cfh −/− RPE. We conclude that deletion of Cfh in the mouse leads to defects in the retina that precede any marked loss of visual function, but which become progressively more marked as the animals age. These observations are consistent with a lifelong role for CFH in retinal homeostasis.

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Complement Factor H Deficiency Results in Decreased Neuroretinal Expression ofCd59ain Aged Mice

Cited by 19 publications

References 35 publications

Exposure to the complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis

Exposure to the complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis

Potential protective function of the sterol regulatory element binding factor 1–fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration

Retinal Changes Precede Visual Dysfunction in the Complement Factor H Knockout Mouse

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