title: AIF-independent parthanatos in the pathogenesis of dry age-related macular degeneration.
abstract: Cell death of retinal pigment epithelium (RPE) is characterized as an essential late-stage phenomenon of dry age-related macular degeneration (AMD). The aim of this study was to elucidate the molecular mechanism underlying RPE cell death after exposure to oxidative stress, which occurs often because of the anatomical location of RPE cells. ARPE-19, an established RPE cell line, exhibited necrotic features involving poly (ADP-ribose) polymerase-1 (PARP-1) activation in response to hydrogen peroxide (H2O2). ARPE-19 cells were resistant to H2O2when PARP-1 was depleted using siRNA or inhibited by a pharmacological inhibitor of PARP-1, olaparib. Our data suggest a causal relationship between PARP-1 activation and ARPE-19 cell death in response to H2O2. Next, we investigated downstream molecular events in PARP-1 activation. Increased mitochondrial depolarization, mitochondrial fission and alterations of the cellular energy dynamics with reduced NAD+ and ATP were observed in H2O2-treated ARPE-19 cells. H2O2-triggered mitochondrial dysfunction was inhibited by olaparib. Nevertheless, translocation of apoptosis-inducing factor (AIF), a biochemical signature for PARP-1-dependent cell death (parthanatos), was not observed in our study. Moreover, the depletion of AIF did not affect the amplitude of cell death, demonstrating the lack of a role for AIF in the death of ARPE-19 cells in response to H2O2. This feature distinguishes the type of death observed in this study from canonical parthanatos. Next, we examined the in vivo role of PARP-1 in a dry AMD animal model system. Histological analysis of the outer nuclear layer in the mouse retina revealed protection against sodium iodate (SI) following treatment with olaparib. Moreover, retina fundus and electroretinograms also confirmed such a protective effect in the SI-treated rabbit. Collectively, we report that AIF-independent PARP-1-dependent necrosis constitutes a major mechanism of RPE cell death leading to retinal degeneration in dry AMD.
authors.affiliation: Department of Biological Sciences, Chungnam National University, Yuseong-gu, Daejeon, Korea.
authors.forename: Ki-Hong
authors.initials: KH
authors.lastname: Jang
authors.affiliation: Department of Biological Sciences, Chungnam National University, Yuseong-gu, Daejeon, Korea.
authors.forename: Yun-Ju
authors.initials: YJ
authors.lastname: Do
authors.affiliation: Department of Biological Sciences, Chungnam National University, Yuseong-gu, Daejeon, Korea.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Son
authors.affiliation: Department of Biological Sciences, Chungnam National University, Yuseong-gu, Daejeon, Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Son
authors.affiliation: Catholic Institute for Visual Science, The Catholic University of Korea, #505 Banpo-dong, Seocho-gu, Seoul, Korea.
authors.forename: Jun-Sub
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Chungnam National University, Yuseong-gu, Daejeon, Korea.|Graduate School of New Drug Discovery and Development, Chungnam National University, Yuseong-gu, Daejeon, Korea.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D057092:Geographic Atrophy / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008268:Macular Degeneration / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009336:Necrosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D051033:Apoptosis Inducing Factor; D010793:Phthalazines; D010879:Piperazines; D006861:Hydrogen Peroxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C531550:olaparib