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Disruption of Ceruloplasmin and Hephaestin in Mice Causes Retinal Iron Overload and Retinal Degeneration with Features of Age-Related Macular Degeneration

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Disruption of Ceruloplasmin and Hephaestin in Mice Causes Retinal Iron Overload and Retinal Degeneration with Features of Age-Related Macular Degeneration Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration Paul Hahn*, Ying Qian*, Tzvete Dentchev*, Lin Chen*, John Beard†, Zena Leah Harris‡, and Joshua L. Dunaief*§ *The F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104; †Department of Nutrition, College of Health and Human Development, Pennsylvania State University, University Park, PA 16802; and ‡Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD 21287 Communicated by Stirling A. Colgate, Los Alamos National Laboratory, Los Alamos, NM, July 30, 2004 (received for review January 10, 2004) Mechanisms of brain and retinal iron homeostasis have become finding further suggests a link between retinal iron overload and subjects of increased interest after the discovery of elevated iron AMD. levels in brains of patients with Alzheimer’s disease and retinas of Ceruloplasmin (Cp) is a multicopper ferroxidase produced by patients with age-related macular degeneration. To determine alternate splicing as either a membrane-linked (8) or secreted whether the ferroxidase ceruloplasmin (Cp) and its homolog hep- protein. The secreted form circulates in the blood but does not cross haestin (Heph) are important for retinal iron homeostasis, we the blood–brain barrier (8). Thus, to function beyond the blood– studied retinas from mice deficient in Cp and͞or Heph. In normal retinal barrier, Cp must be expressed in the retina. Within the mice, Cp and Heph localize to Mu¨ller glia and retinal pigment normal human and mouse retinas, Cp expression was detected in epithelium, a blood–brain barrier. Mice deficient in both Cp and the inner nuclear layer (9, 10), with increased expression in the Heph, but not each individually, had a striking, age-dependent inner nuclear layer and ganglion cell layer after optic nerve crush increase in retinal pigment epithelium and retinal iron. The iron (11) and an increase in Mu¨ller glia after photic injury (12). storage protein ferritin was also increased in Cp؊͞؊Heph؊͞Y Evidence suggests that Cp facilitates iron export from cells. By retinas. After retinal iron levels had increased, Cp؊͞؊Heph؊͞Y oxidizing ferrous to ferric iron, the only form that can be taken up mice had age-dependent retinal pigment epithelium hypertrophy, by the serum transport protein, transferrin, Cp may establish an ion hyperplasia and death, photoreceptor degeneration, and subreti- gradient favoring iron export. In vitro, Cp is necessary for iron nal neovascularization, providing a model of some features of the export from brain astrocytes (13) and can facilitate iron export from Ϫ͞Ϫ human retinal diseases aceruloplasminemia and age-related mac- macrophages (14). Further, Cp mice have impaired liver iron Ϫ͞Ϫ ular degeneration. This pathology indicates that Cp and Heph are efflux (15). Unlike humans with aceruloplasminemia, our Cp mice do not manifest significant CNS iron overload or neuropathy critical for CNS iron homeostasis and that loss of Cp and Heph in the Ϫ͞Ϫ mouse leads to age-dependent retinal neurodegeneration, provid- even at 24 months. An independently generated Cp mouse ing a model that can be used to test the therapeutic efficacy of iron showed mild CNS iron overload, and cells from these mice had chelators and antiangiogenic agents. increased susceptibility to oxidative stress (16). One potential explanation for the lack of severe CNS iron overload in CpϪ͞Ϫ mice is that hephaestin (Heph), another ron is an essential cofactor in heme and nonheme-containing multicopper ferroxidase with 50% identity to Cp, may also facilitate 2ϩ Ienzymes, but ferrous iron (Fe ) generates free radicals that can iron export. Heph is naturally mutated in the sex-linked anemia (sla) cause oxidative damage via the Fenton reaction. Homeostatic mouse (17). Because Heph is a membrane-bound protein that regulation of ferrous iron levels is critical for meeting physiologic mediates iron egress from intestinal enterocytes into the circulation demand while preventing the toxicity associated with iron overload. (17), sla mice are anemic as a result of impaired intestinal iron Consistent with a need for precise regulation of retinal iron, absorption. The Heph mutation in the sla mouse is a deletion of two iron overload can cause retinal degenerations. Iron retained in exons resulting in a predicted deletion of 194 aa. As a result, sla mice the eye as a foreign body or injected into the vitreous causes have significantly diminished Heph ferroxidase activity (18). photoreceptor degeneration, demonstrating that iron overload is Before the present study, Heph had not to our knowledge been toxic to photoreceptors (1–3). A comparison of postmortem studied in the retina. To test the hypothesis that deficiency of both retinas from age-related macular degeneration (AMD) and Cp and Heph would induce retinal iron overload and neurodegen- normal donors documented increased iron within the retinal eration, we generated mice harboring both our Cp knockout allele pigment epithelium (RPE) (4), a cellular monolayer forming the and the sex-linked Heph mutation from sla mice and studied male blood-retinal barrier and nourishing photoreceptors. These re- mice herein referred to as CpϪ͞ϪHephϪ͞Y mice. We find that sults suggest that iron overload may play a role in the patho- combined deficiency of Cp and Heph results in retinal iron accu- genesis of AMD, a retinal degeneration that is the most common mulation with secondary increases in several forms of the iron cause of irreversible vision loss in the U.S. storage protein ferritin and, ultimately, retinal degeneration. Iron overload is also implicated in the retinal degeneration occurring in patients with the rare autosomal recessive disease Methods aceruloplasminemia. These patients have pathologic accumulation Generation of Mice and Fixation of Eyes. C57BL͞6 mice with a of iron in liver, spleen, pancreas, retina, and basal ganglia by the targeted mutation in the Cp gene (CpϪ͞Ϫ) (15), C57BL͞6 mice fourth or fifth decade of life (5, 6). Five Japanese patients all had with the naturally occurring sla mutation in the Heph gene (des- pigmentary retinopathy by their fifth decade (5–7). Although ignated herein as HephϪ͞Y,asHeph resides on the X chromo- histopathology has not been published, one patient had retinal iron overload in unspecified cell types (6). One Caucasian patient with Abbreviations: Cp, ceruloplasmin; Heph, hephaestin; AMD, age-related macular degener- undetectable serum ceruloplasmin had drusen, yellowish white ation; RPE, retinal pigment epithelium; CRALBP, cellular retinaldehyde binding protein; spots under the retina that constitute the defining clinical feature DAB, 3,3’-diaminobenzidine. of AMD (J.L.D., unpublished results). Because this patient’s §To whom correspondence should be addressed. E-mail: [email protected]. drusen were first detected at age 46, an early onset of AMD, this © 2004 by The National Academy of Sciences of the USA 13850–13855 ͉ PNAS ͉ September 21, 2004 ͉ vol. 101 ͉ no. 38 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0405146101 Downloaded by guest on September 29, 2021 some), and mice generated by crossing both single knockout mice Sterling Heights, MI) with IMAGEPRO PLUS software, Version 4.1 (CpϪ͞ϪHephϪ͞Y) were studied. Eyes were enucleated immedi- (Media Cybernetics, Silver Spring, MD). ately after death and fixed overnight in 4% paraformaldehyde with or without 0.5% glutaraldehyde or in 10% formalin. In addition, Quantitative Iron Detection. Retinas from WT, CpϪ͞Ϫ, WT C57BL͞6 and BALB͞c eyes were enucleated and lightly fixed HephϪ͞Y, and CpϪ͞ϪHephϪ͞Y mice were dissected from the in 4% paraformaldehyde for 2 h before use for immunohistochem- underlying RPE͞choroid͞sclera. Iron in these tissues was mea- istry. All procedures were approved by the Institutional Animal sured by graphite furnace atomic absorption spectrophotometry Care and Use Committee of the University of Pennsylvania. (model 5100 AA, PerkinElmer) by using standard methods (20). Human eyes were obtained from the National Disease Research Interchange through a protocol approved by the University of Electron Microscopy and Energy-Dispersive X-Ray Spectroscopy. Ret- Pennsylvania Institutional Review Board. They were enucleated 3 h inas (including RPE) fixed in 2% paraformaldeyhyde, 2% glutar- postmortem and kept on ice until retinas were dissected 24 h later aldehyde were postfixed in 1% osmium tetroxide, 0.1 M sodium and used for Western analysis. cacodylate buffer. Specimens were dehydrated and embedded in Epon (Ted Pella, Inc., Redding, CA). Ultrathin sections were cut, Dissection of Murine RPE and Retinas for RT-PCR and Western Analysis. stained with uranyl acetate, and examined with a JEOL 1010 C57BL͞6 mice were killed, and eyes were promptly enucleated. transmission electron microscope. Semithin 1- to 3-␮m sections Anterior segments were removed, and retinas were completely were stained with toluidine blue or methylene blue͞azure II and dissected away from the underlying RPE. Retinas were then analyzed by light microscopy as described above. flash-frozen and stored at Ϫ80°C. RPE was enzymatically detached Energy-dispersive x-ray spectroscopy was performed with from the remaining posterior segment by incubation in 0.25% scanning mode, and spectra were collected with a Kevex 8000 trypsin
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