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

• Published in: The American journal of pathology Vol. 173; no. 5; pp. 1326 - 1338
• Main Authors: Murakami, Yusuke, Ikeda, Yasuhiro, Yonemitsu, Yoshikazu, Onimaru, Mitsuho, Nakagawa, Kazunori, Kohno, Ri-ichiro, Miyazaki, Masanori, Hisatomi, Toshio, Nakamura, Makoto, Yabe, Takeshi, Hasegawa, Mamoru, Ishibashi, Tatsuro, Sueishi, Katsuo
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.11.2008; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Apoptosis - drug effects; Apoptosis Inducing Factor - genetics; Apoptosis Inducing Factor - metabolism; Biological and medical sciences; Caspases - metabolism; Cell Line; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Chromosome aberrations; Cytoprotection - drug effects; Disease Models, Animal; Eye Proteins - metabolism; Eye Proteins - pharmacology; Humans; Investigative techniques, diagnostic techniques (general aspects); Medical genetics; Medical sciences; Mitochondria - drug effects; Mitochondria - metabolism; Nerve Growth Factors - metabolism; Nerve Growth Factors - pharmacology; Neurons - cytology; Neurons - drug effects; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Photoreceptor Cells - drug effects; Photoreceptor Cells - metabolism; Protein Transport - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Regular; Retinal Degeneration - metabolism; Retinal Degeneration - pathology; Serpins - metabolism; Serpins - pharmacology; Serum; Signal Transduction - drug effects; Transduction, Genetic; Up-Regulation - drug effects; Chromosomal aberration; Animal model; Neuroprotection; Retinopathy; Rat; Rodentia; Essential; Biological activity; Mechanism; Macular degeneration; Eye disease; Vertebrata; Anatomic pathology; Mammalia; Cytogenetics; Abnormal chromosome; Inhibitor; Inhibition; Pigment epithelium-derived factor; Transcription factor; Apoptosis inducing factor; Chromosome translocation
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2008.080466

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.