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 H2O2 when 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.

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

“…Although the clear focus with olaparib -both preclinically and clinically -has been the therapy of various cancers, several groups have started conducting preclinical studies with olaparib in the context of various non-oncological applications, with an eye on future therapeutic repurposing. These efforts, so far, have demonstrated (1) protective effects of olaparib in vitro against NMDA receptor stimulation induced or oxygen-glucose deprivation induced death in differentiated human neurons (Xu et al, 2016) and in retinal pigment epithelial cell lines exposed to H 2 O 2 (Jang et al, 2017) and in cisplatin-induced injury in chronic myeloid leukaemia cells (Xiao and Kan, 2017), (2) protective effects of olaparib in a mouse model of transient middle cerebral artery occlusion and reperfusion (Teng et al, 2016), (3) protective effects of olaparib in various models of model of lung injury/lung inflammation, either induced by endotoxin (Kapoor et al, 2015) or in asthma models elicited by senzitization to ovalbumin (Ghonim et al, 2015a) or to house dust mites (Ghonim et al, 2015b), (4) protective effects of olaparib in various models of multiple organ dysfunction, either elicited by bacterial lipopolysaccharide (Kapoor et al, 2015) or by third-degree thermal injury (Ahmad et al, 2018), and (5) protective effects of olaparib in rodent models of acute and chronic liver failure Mukhopadhyay et al, 2017). The current data confirm and extend these findings and demonstrate the protective effect of olaparib in oxidant-challenged cardiac myocytes and in transplanted rat hearts.…”

ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage

“… 17 , 18 , 19 , 20 , 21 , 22 In addition, alkylation damage can induce the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus, where AIF forms a DNA-degrading complex with histone H2AX and cyclophilin D. 10 , 23 Alkylation-induced necrosis appears to be distinct from caspase-dependent apoptosis or receptor-mediated necroptosis as neither caspase nor necroptosis inhibitors can rescue alkylation-induced necrotic cell death. 24 , 25 , 26 , 27 …”

Oxidative stress in retinal pigment epithelial cells increased endogenous complement-dependent inflammatory and angiogenic responses - independent from exogenous complement sources

“…This correlation between 225 complement components, foxp3 expression and pro-angiogenic reaction in RPE cells needs to be 226 further investigated. Oxidative stress-induced cellular reactions were previously ameliorated by an approved anti-cancer 232 drug olaparib, which is an inhibitor of the poly(ADP-ribose) polymerase (PARP) [40][41][42]. We 233 investigated the effect of olaparib on H 2 O 2 -dependent mRNA expression changes of complement 234 receptors, components and inflammation-related transcripts (Fig.…”

“…Oxidative stress-related cell damage of ARPE-19 cells and retinal degeneration in mouse models for 325 RPE degeneration as well as hereditary retinal degeneration were successfully ameliorated using 326 olaparib in previous studies [40][41][42]. Olaparib is a clinically developed poly-ADP-ribose-polymerase 327 inhibitor developed for cancer treatment by blocking the DNA-repair mechanism.…”

“…Olaparib is a clinically developed poly-ADP-ribose-polymerase 327 inhibitor developed for cancer treatment by blocking the DNA-repair mechanism. ARPE-19 cells were 328 resistant to H 2 O 2 induced mitochondrial dysfunction and to energy failure, when olaparib was added 329 [40]. We ask the question if olaparib can also normalize complement-associated pro-inflammatory Oxidative stress and activation of the complement system cause retinal degeneration, but the 337 mechanism behind this is still a matter of investigation.…”