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.
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.
Murakami
Yusuke
Y
Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, 812-8582, Japan.
Ikeda
Yasuhiro
Y
Yonemitsu
Yoshikazu
Y
Onimaru
Mitsuho
M
Nakagawa
Kazunori
K
Kohno
Ri-ichiro
R
Miyazaki
Masanori
M
Hisatomi
Toshio
T
Nakamura
Makoto
M
Yabe
Takeshi
T
Hasegawa
Mamoru
M
Ishibashi
Tatsuro
T
Sueishi
Katsuo
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D010786:Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology*; D015843:Serpins / Q000378:metabolism* / Q000494:pharmacology; D044967:Serum; D015398:Signal Transduction / Q000187:drug effects; D014161:Transduction, Genetic; D015854:Up-Regulation / Q000187:drug effects; D000099174:Pigment Epithelium-Derived Factor
D051033:Apoptosis Inducing Factor; D020169:Caspases; D005136:Eye Proteins; D009414:Nerve Growth Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor