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Yasuhiro Ikeda, Yusuke Murakami, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Tatsuro Ishibashi; Oxidative DNA Damage Plays a Key Role in the Process of Photoreceptor Death in Inherited Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1828.
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We have recently demonstrated that apoptosis-inducing factor (AIF) is an essential executioner of photoreceptor apoptosis in inherited retinal degeneration. However, the upstream pathway, which triggers the release of AIF from mitochondria, remains unknown. Accumulation of oxidative DNA damage is associated with various neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, and causes the AIF release via poly(ADP-ribose) polymerase (PARP) activation. Therefore, we investigated whether these pathways are involved in the photoreceptor apoptosis in rd10 mice, a mouse model of inherited retinal degeneration.
Eyes from rd10 mice, which have a missense mutation in Pde6b, and wild-type C57BL6 mice were used for the experiments. Accumulation of8-oxo-7,8-dihydroguanine (8-oxo-dG), a major oxidative base lesion in DNA or nucleotides, were analyzed by immunohistochemisty. Single strand DNA breaks and PAR expression, a product of PARP activation, were assessed by immunofluoresence. Rd10 mice received daily intraperitoneal injection of PARP inhibitor, 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ; 20 µg/g/day) or vehicle (1% DMSO in PBS), and the retinas were subjected to histological assessments.
Immunohistochemical analysis showed that 8-oxo-dG staining increased in photoreceptors of rd10 mice, especially of their nuclei, at 21 days after birth. Immunofluorescence for single strand DNA and PAR showed intense staining in photoreceptor nuclei of rd10 mice. PARP inhibition by PARP inhibitor DPQ attenuated the photoreceptor loss in rd10 mice at 26 days after birth, compared with vehicle treatment.
DNA oxidation increases in photoreceptors, especially of their nuclei, from an early phase of inherited retinal degeneration, and may play a key role to initiate photoreceptor death via PARP activation.
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