Department of Ophthalmic Research, Cole Eye Institute & Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH, 44195, USA; Cleveland Clinic Lerner College of Medicine, Dept. of Molecular Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
Department of Ophthalmic Research, Cole Eye Institute & Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH, 44195, USA.
Redox Biol. 2020 Oct;37:101681. doi: 10.1016/j.redox.2020.101681. Epub 2020 Aug 10.
Sorsby Fundus Dystrophy (SFD) is a rare inherited autosomal dominant macular degeneration caused by specific mutations in TIMP3. Patients with SFD present with pathophysiology similar to the more common Age-related Macular Degeneration (AMD) and loss of vision due to both choroidal neovascularization and geographic atrophy. Previously, it has been shown that RPE degeneration in AMD is due in part to oxidative stress. We hypothesized that similar mechanisms may be at play in SFD. The objective of this study was to evaluate whether mice carrying the S179C-Timp3 mutation, a variant commonly observed in SFD, showed increased sensitivity to oxidative stress. Antioxidant genes are increased at baseline in the RPE in SFD mouse models, but not in the retina. This suggests the presence of a pro-oxidant environment in the RPE in the presence of Timp3 mutations. To determine if the RPE of Timp3 mutant mice is more susceptible to degeneration when exposed to low levels of oxidative stress, mice were injected with low doses of sodium iodate. The RPE and photoreceptors in Timp3 mutant mice degenerated at low doses of sodium iodate, which had no effect in wildtype control mice. These studies suggest that TIMP3 mutations may result in a dysregulation of pro-oxidant-antioxidant homeostasis in the RPE, leading to RPE degeneration in SFD.
桑德斯眼底营养不良症（SFD）是一种罕见的遗传性常染色体显性黄斑变性，由 TIMP3 中的特定突变引起。SFD 患者的病理生理学与更为常见的年龄相关性黄斑变性（AMD）相似，由于脉络膜新生血管和地图状萎缩，视力丧失。先前已经表明，AMD 中的 RPE 变性部分归因于氧化应激。我们假设在 SFD 中可能存在类似的机制。本研究的目的是评估携带 S179C-Timp3 突变的小鼠（SFD 中常见的一种变体）是否对氧化应激更敏感。在 SFD 小鼠模型中，RPE 中的抗氧化基因在基线时增加，但在视网膜中没有增加。这表明在存在 TIMP3 突变的情况下，RPE 中存在促氧化环境。为了确定在暴露于低水平氧化应激时 Timp3 突变小鼠的 RPE 是否更容易发生变性，用低剂量的碘酸钠对小鼠进行了注射。Timp3 突变小鼠的 RPE 和光感受器在低剂量的碘酸钠下发生变性，而在野生型对照小鼠中没有这种作用。这些研究表明，TIMP3 突变可能导致 RPE 中促氧化剂-抗氧化剂平衡的失调，从而导致 SFD 中的 RPE 变性。
