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Originally published online as doi:10.2353/ajpath.2008.080466 on October 9, 2008

Published online before print October 9, 2008
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(American Journal of Pathology. 2008;173:1326-1338.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080466

Inhibition of Nuclear Translocation of Apoptosis-Inducing Factor Is an Essential Mechanism of the Neuroprotective Activity of Pigment Epithelium-Derived Factor in a Rat Model of Retinal Degeneration

Yusuke Murakami*{dagger}, Yasuhiro Ikeda{dagger}, Yoshikazu Yonemitsu{ddagger}, Mitsuho Onimaru*, Kazunori Nakagawa*, Ri-ichiro Kohno{dagger}, Masanori Miyazaki{dagger}, Toshio Hisatomi{dagger}, Makoto Nakamura§, Takeshi Yabe, Mamoru Hasegawa||, Tatsuro Ishibashi{dagger} and Katsuo Sueishi*

From the Department of Pathology,* Division of Pathophysiological and Experimental Pathology, and the Department of Ophthalmology,{dagger} Graduate School of Medical Sciences, Kyushu University, Fukuoka; the Department of Gene Therapy,{ddagger} Chiba University Graduate School of Medicine, Chiba; the Department of Organs Therapeutics,§ Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe; the Kitasato Institute for Life Sciences, Kitasato University, Tokyo; and DNAVEC Corporation,|| Ibaraki, Japan

Photoreceptor apoptosis is a critical process of retinal degeneration in retinitis pigmentosa (RP), a group of retinal degenerative diseases that result from rod and cone photoreceptor cell death and represent a major cause of adult blindness. We previously demonstrated the efficient prevention of photoreceptor apoptosis by intraocular gene transfer of pigment epithelium-derived factor (PEDF) in animal models of RP; however, the underlying mechanism of the neuroprotective activity of PEDF remains elusive. In this study, we show that an apoptosis-inducing factor (AIF)-related pathway is an essential target of PEDF-mediated neuroprotection. PEDF rescued serum starvation-induced apoptosis, which is mediated by AIF but not by caspases, of R28 cells derived from the rat retina by preventing translocation of AIF into the nucleus. Nuclear translocation of AIF was also observed in the apoptotic photoreceptors of Royal College of Surgeons rats, a well-known animal model of RP that carries a mutation of the Mertk gene. Lentivirus-mediated retinal gene transfer of PEDF prevented the nuclear translocation of AIF in vivo, resulting in the inhibition of the apoptotic loss of their photoreceptors in association with up-regulated Bcl-2 expression, which mediates the mitochondrial release of AIF. These findings clearly demonstrate that AIF is an essential executioner of photoreceptor apoptosis in inherited retinal degeneration and provide a therapeutic rationale for PEDF-mediated neuroprotective gene therapy for individuals with RP.






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Copyright © 2008 by the American Society for Investigative Pathology.