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
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
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DOI：
10.2353/ajpath.2008.080466
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发表时间：
2008-11-01
影响因子：
6
通讯作者：
Sueishi, Katsuo
中科院分区：
文献类型：
--
作者：
Murakami, Yusuke;Ikeda, Yasuhiro;Sueishi, Katsuo
视网膜色素变性（retinitis pigmentosa，RP）是一组由视杆细胞和视锥细胞死亡引起的视网膜变性疾病，是成人致盲的主要原因，光感受器凋亡是RP视网膜变性的关键过程。我们以前证明了有效的预防感光细胞凋亡的眼内基因转移色素上皮衍生因子（PEDF）在RP的动物模型，然而，PEDF的神经保护活性的潜在机制仍然难以捉摸。在这项研究中，我们表明，骨化诱导因子（AIF）相关的途径是PEDF介导的神经保护的重要目标。PEDF通过阻止AIF易位到细胞核中来挽救血清饥饿诱导的大鼠视网膜R28细胞凋亡，该凋亡由AIF介导，而不是由半胱天冬酶介导。在皇家外科学院大鼠的凋亡光感受器中也观察到AIF的核易位，所述大鼠是携带Merik基因突变的RP的众所周知的动物模型。慢病毒介导的PEDF视网膜基因转移在体内阻止了AIF的核转位，导致其光感受器的凋亡损失的抑制与上调Bcl-2表达相关，其介导了A-IF的线粒体释放。这些发现清楚地表明，AIF是遗传性视网膜变性中感光细胞凋亡的重要执行者，并为RP患者的PEDF介导的神经保护基因治疗提供了治疗依据。(Am J Pathol 2008，173：1326-1338; DOI：10.2353/ajpath.2008.080466）
Photoreceptor apoptosis is a critical process of retina degeneration in retinitis pigmentosa (RP), a group 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 Merik 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 A-IF. 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. (Am J Pathol 2008, 173:1326-1338; DOI: 10.2353/ajpath.2008.080466)