AIF-independent parthanatos in the pathogenesis of dry age-relatedmacular degeneration

Collection with item attached
2017
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/474380.do
DOI
10.1038/cddis.2016.437
Title
AIF-independent parthanatos in the pathogenesis of dry age-relatedmacular degeneration
Description
This research was supported by the Bio & Medical Technology DevelopmentProgram of the National Research Foundation (NRF) funded by the Koreangovernment (MSIP) (No. NRF-2014M3A9A8064469).
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 degenerati
provenance
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language
English
author
Jang, Ki-Hong
Do, Yun-Ju
Son, Dongwon
Son, Eunji
Choi, Jun-Sub
Kim, Eunhee
accessioned
2018-09-28T10:44:32Z
available
2018-09-28T10:44:32Z
issued
2017
citation
CELL DEATH & DISEASE(8)
issn
2041-4889
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/474380.do
Funder
교육부
Funding Program
BK21플러스사업(0.5)
Project ID
1345273974
Jurisdiction
Rep.of Korea
Project Name
Glocal BioBrain Center for Daedeok R&D Innopolis
rights
openAccess
type
article


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