Department of Ophthalmology, Osaka University Medical School, Suita, Japan.
Pain and Neuroscience Laboratories, Daiichi Sankyo Co, Ltd, Tokyo, Japan.
Am J Pathol. 2018 Dec;188(12):2729-2744. doi: 10.1016/j.ajpath.2018.08.012. Epub 2018 Sep 29.
Age-related macular degeneration (AMD) is an important cause of blindness. It is characterized by a retinal pigment epithelium (RPE) disorder that leads to death of photoreceptor cells (PRCs). AMD has a strong genetic association with high-temperature requirement A 1 (HTRA1). The relationship between HTRA1 and the AMD phenotype is unknown. In this study, we show that the expression of HTRA1 in PRCs, as well as in RPE, is increased by the disease-associated HTRA1 mutation and aging. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and quantitative PCR of apoptosis-associated caspases confirmed that PRC-specific overexpression of HTRA1 induced PRC death. Transgenic zebrafish overexpressing human HTRA1 in rod PRCs showed morphologic changes of the RPE, including PRC death and lipofuscin accumulation, features similar to those of early AMD. htra1 expression was also increased in a retinitis pigmentosa zebrafish model compared with wild type. In both fish lines, PRC death was rescued by the suppression of htra1 by the inhibitor 6-boroV. AKT-forkhead box O3 signaling downstream of HTRA1 was activated via a tumor growth factor β signal, resulting in PRC death. These findings suggest that HTRA1 derived from PRCs is associated with early AMD via PRC death. HTRA1 is a potentially effective target for neuroprotective therapy of early AMD and other degenerative diseases of PRCs.
年龄相关性黄斑变性（AMD）是失明的重要原因。它的特征是视网膜色素上皮（RPE）紊乱，导致光感受器细胞（PRC）死亡。AMD 与高温需求 A1（HTRA1）有很强的遗传关联。HTRA1 与 AMD 表型之间的关系尚不清楚。在这项研究中，我们表明，疾病相关的 HTRA1 突变和衰老会增加 PRC 和 RPE 中 HTRA1 的表达。末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记测定和凋亡相关半胱天冬酶的定量 PCR 证实，PRC 特异性过表达 HTRA1 诱导 PRC 死亡。在杆状 PRC 中过表达人 HTRA1 的转基因斑马鱼表现出 RPE 的形态变化，包括 PRC 死亡和脂褐素积累，这与早期 AMD 的特征相似。与野生型相比，在视网膜色素变性斑马鱼模型中 htra1 的表达也增加了。在这两种鱼系中，通过抑制剂 6-boroV 抑制 htra1 可挽救 PRC 死亡。HTRA1 下游的 AKT-forkhead box O3 信号通过转化生长因子 β 信号被激活，导致 PRC 死亡。这些发现表明，来源于 PRC 的 HTRA1 通过 PRC 死亡与早期 AMD 相关。HTRA1 是早期 AMD 和其他 PRC 退行性疾病神经保护治疗的潜在有效靶点。
