HTRA1-dependent proteolysis induces age-related retinal degeneration and exacerbates choroidal neovascularization.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-10-01 Epub Date: 2025-09-17 DOI:10.1242/dmm.052253
Kenneth J Katschke, Tom Truong, Victoria Pham, Hongkang Xi, Wanjian Tang, Xiaowu Gu, Pooja Teotia, Jeffrey W Hofmann, Shawnta Y Chaney, Daniel Kirchhofer, Menno van Lookeren Campagne, Marion Jeanne
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引用次数: 0

Abstract

Polymorphisms in the ARMS2/HTRA1 locus on chromosome 10 enhance the risk of geographic atrophy and macular neovascularization, the advanced forms of age-related macular degeneration (AMD). Although HTRA1 mutations have been associated with microvascular defects in the brain, it remains unclear whether changes in HTRA1 expression contribute to AMD pathophysiology. In this study, we showed that, in AMD donor eyes, HTRA1 protein accumulated around the retinal pigment epithelium (RPE)/photoreceptor lesions. We then demonstrated that overexpression of catalytically active, but not catalytically inactive, HTRA1 in RPE cells in mice induced age-dependent loss of photoreceptors, inflammation and a decline in photoreceptor functional responses. This retinal degeneration was not exacerbated when the mice were exposed to phototoxic stress in the constant light exposure preclinical model. However, mice overexpressing catalytically active HTRA1 had significant exacerbation of laser-induced choroidal neovascularization lesions. Finally, as substrate processing may define the molecular basis for HTRA1-induced retinal degeneration, we initiated a proteomics approach and identified the visual cycle key player RBP3 as a disease-relevant HTRA1 substrate in the retina.

htra1依赖性蛋白水解诱导年龄相关性视网膜变性并加剧脉络膜新生血管。
10号染色体ARMS2/HTRA1位点的多态性增加了地理萎缩(GA)和黄斑新生血管(MNV)的风险,这是年龄相关性黄斑变性(AMD)的晚期形式。虽然HTRA1突变与大脑微血管缺陷有关,但尚不清楚HTRA1表达的变化是否与AMD的病理生理有关。在本研究中,我们发现在AMD供体眼中,HTRA1蛋白在视网膜色素上皮(RPE)/光感受器病变周围积聚。我们随后证明,在小鼠RPE细胞中,催化活性而非催化无活性的HTRA1的过度表达会诱导光感受器的年龄依赖性丧失、炎症和光感受器功能反应的下降。在持续光暴露(CLE)临床前模型中,当小鼠暴露于光毒性应激时,这种视网膜变性没有加剧。然而,过度表达具有催化活性的HTRA1的小鼠会显著加剧激光诱导的脉络膜新生血管(CNV)病变。最后,由于底物加工可以确定HTRA1诱导视网膜变性的分子基础,我们启动了蛋白质组学方法,并确定视觉周期关键参与者RBP3是视网膜中与疾病相关的HTRA1底物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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