High-Temperature Requirement A 1 Causes Photoreceptor Cell Death in Zebrafish Disease Models
High-Temperature Requirement A 1 Causes Photoreceptor Cell Death in Zebrafish Disease Models
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DOI：
10.1016/j.ajpath.2018.08.012
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发表时间：
2018-12-01
影响因子：
6
通讯作者：
Nishida, Kohji
中科院分区：
文献类型：
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作者：
Oura, Yoshihito;Nakamura, Machiko;Nishida, Kohji
老年性黄斑变性(AMD)是导致失明的重要原因。它的特点是视网膜色素上皮(RPE)紊乱，导致光感受器细胞(PRCs)死亡。AMD与高温需求A1(HTRA1)有很强的遗传关联。HTRA1与AMD表型的关系尚不清楚。在这项研究中，我们发现HTRA1在PRC和RPE中的表达随着疾病相关的HTRA1突变和年龄的增加而增加。末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法和凋亡相关半胱氨酸天冬氨酸氨基转移酶的定量聚合酶链式反应证实了PRC特异性的HTRA1过表达导致了PRC死亡。在杆状PRC中高表达人HTRA1的转基因斑马鱼表现出与早期AMD相似的RPE的形态变化，包括PRC死亡和脂褐素积聚。与野生型相比，视网膜色素变性斑马鱼模型中HTRA1的表达也增加。在这两个鱼种中，6-Borov抑制剂对HTRA1的抑制挽救了PRC的死亡。HTRA1下游的AKT叉头盒03信号通过肿瘤生长因子β信号被激活，导致PRC死亡。这些发现表明，来源于PRC的HTRA1与早期AMD通过PRC死亡有关。HTRA1是治疗早期AMD和其他原发灶退行性疾病的神经保护治疗的潜在有效靶点。
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 03 signaling downstream of HTRA1 was activated via a tumor growth factor beta 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.