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线粒体 μ-钙蛋白酶抑制肽可防止 S334ter 转染视紫红质和 P23H 大鼠的光感受器变性。

Inhibitory peptide of mitochondrial μ-calpain protects against photoreceptor degeneration in rhodopsin transgenic S334ter and P23H rats.

机构信息

Department of Ophthalmology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

出版信息

PLoS One. 2013 Aug 9;8(8):e71650. doi: 10.1371/journal.pone.0071650. eCollection 2013.

Abstract

Mitochondrial μ-calpain and apoptosis-inducing factor (AIF)-dependent photoreceptor cell death has been seen in several rat and mouse models of retinitis pigmentosa (RP). Previously, we demonstrated that the specific peptide inhibitor of mitochondrial μ-calpain, Tat-µCL, protected against retinal degeneration following intravitreal injection or topical eye-drop application in Mertk gene-mutated Royal College of Surgeons rats, one of the animal models of RP. Because of the high rate of rhodopsin mutations in RP patients, the present study was performed to confirm the protective effects of Tat-µCL against retinal degeneration in rhodopsin transgenic S334ter and P23H rats. We examined the effects of intravitreal injection or topical application of the peptide on retinal degeneration in S334ter and P23H rats by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, electroretinogram (ERG), immunohistochemistry for AIF, and histological staining. In S334ter rats, we found that intravitreal injection or topical application of the peptide prevented photoreceptor cell death from postnatal (PN) 15 to 18 days, the time of early-stage retinal degeneration. Topical application of the peptide also delayed attenuation of ERG responses from PN 28 to 56 days. In P23H rats, topical application of the peptide protected against photoreceptor cell death and nuclear translocation of AIF on PN 30, 40, and 50 days, as the primary stages of degeneration. We observed that topical application of the peptide inhibited the thinning of the outer nuclear layer and delayed ERG attenuations from PN 30 to 90 days. Our results demonstrate that the mitochondrial μ-calpain and AIF pathway is involved in early-stage retinal degeneration in rhodopsin transgenic S334ter and P23H rats, and inhibition of this pathway shows curative potential for rhodopsin mutation-caused RP.

摘要

在几种视网膜色素变性(RP)的大鼠和小鼠模型中已经观察到线粒体 μ-钙蛋白酶和凋亡诱导因子(AIF)依赖性光感受器细胞死亡。以前,我们证明了线粒体 μ-钙蛋白酶的特异性肽抑制剂 Tat-µCL,在 Mertk 基因突变 Royal College of Surgeons 大鼠(一种 RP 的动物模型)中,通过玻璃体内注射或局部滴眼应用,可防止视网膜变性。由于 RP 患者视紫红质突变率较高,因此进行了本研究以确认 Tat-µCL 对视紫红质转染 S334ter 和 P23H 大鼠视网膜变性的保护作用。我们通过末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记(TUNEL)测定、视网膜电图(ERG)、AIF 的免疫组织化学和组织学染色,检查了肽的玻璃体内注射或局部应用对 S334ter 和 P23H 大鼠视网膜变性的影响。在 S334ter 大鼠中,我们发现肽的玻璃体内注射或局部应用可防止光感受器细胞从出生后(PN)15 天到 18 天的早期视网膜变性死亡,即早期阶段的视网膜变性。肽的局部应用也延迟了从 PN 28 天到 56 天的 ERG 反应衰减。在 P23H 大鼠中,肽的局部应用可防止光感受器细胞死亡和 AIF 的核转位,在 PN 30、40 和 50 天,即变性的主要阶段。我们观察到,肽的局部应用抑制了外核层的变薄,并从 PN 30 天到 90 天延迟了 ERG 的衰减。我们的结果表明,线粒体 μ-钙蛋白酶和 AIF 途径参与了视紫红质转染 S334ter 和 P23H 大鼠的早期视网膜变性,抑制该途径对视紫红质突变引起的 RP 具有治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc8/3739725/cf4e70d138ef/pone.0071650.g001.jpg

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