Duke Eye Center, Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA; Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan.
Departments of Ophthalmology and Radiology, Neuroscience Institute, and Tech4Health Institute, New York University Grossman School of Medicine, New York, NY 10017, USA.
Vision Res. 2024 Nov;224:108463. doi: 10.1016/j.visres.2024.108463. Epub 2024 Aug 28.
Optineurin (OPTN) is a gene associated with familial normal tension glaucoma (NTG). While NTG involves intraocular pressure (IOP)-independent neurodegeneration of the visual pathway that progresses with age, how OPTN dysfunction leads to NTG remains unclear. Here, we generated an OPTN knockout mouse (Optn) model to test the hypothesis that a loss-of-function mechanism induces structural and functional eye deterioration with aging. Eye anatomy, visual function, IOP, retinal histology, and retinal ganglion cell survival were compared to littermate wild-type (WT) control mice. Consistent with OPTN's role in NTG, loss of OPTN did not increase IOP or alter gross eye anatomy in young (2-3 months) or aged (12 months) mice. When retinal layers were quantitated, young Optn mice had thinner retina in the peripheral regions than young WT mice, primarily due to thinner ganglion cell-inner plexiform layers. Despite this, visual function in Optn mice was not severely impaired, even with aging. We also assessed relative abundance of retinal cell subtypes, including amacrine cells, bipolar cells, cone photoreceptors, microglia, and astrocytes. While many of these cellular subtypes were unaffected by Optn deletion, more dopaminergic amacrine cells were observed in aged Optn mice. Taken together, our findings showed that complete loss of Optn resulted in mild retinal changes and less visual function impairment, supporting the possibility that OPTN-associated glaucoma does not result from a loss-of-function disease mechanism. Further research using these Optn mice will elucidate detailed molecular pathways involved in NTG and identify clinical or environmental risk factors that can be targeted for glaucoma treatment.
视神经病变诱导蛋白（Optineurin，OPTN）是一种与家族性正常眼压型青光眼（normal tension glaucoma，NTG）相关的基因。尽管 NTG 涉及眼压（intraocular pressure，IOP）独立的视觉通路神经退行性变，且随年龄增长而进展，但 OPTN 功能障碍如何导致 NTG 仍不清楚。在这里，我们构建了 OPTN 敲除小鼠（Optn）模型，以测试功能丧失机制是否会导致结构和功能随年龄恶化的假说。比较了眼部解剖结构、视觉功能、IOP、视网膜组织学和视网膜神经节细胞存活情况，与同窝野生型（WT）对照小鼠进行比较。与 OPTN 在 NTG 中的作用一致，在年轻（2-3 个月）或年老（12 个月）小鼠中，缺失 OPTN 并未增加 IOP 或改变眼球大体解剖结构。当定量视网膜层时，年轻的 Optn 小鼠的周边区域视网膜比年轻的 WT 小鼠更薄，主要是因为神经节细胞-内丛状层更薄。尽管如此，即使随着年龄的增长，Optn 小鼠的视觉功能也没有严重受损。我们还评估了视网膜细胞亚型的相对丰度，包括无长突细胞、双极细胞、视锥细胞、小胶质细胞和星形胶质细胞。尽管许多这些细胞亚型不受 Optn 缺失的影响，但在年老的 Optn 小鼠中观察到更多的多巴胺能无长突细胞。综上所述，我们的研究结果表明，Optn 的完全缺失导致轻度的视网膜变化和较少的视觉功能障碍，这支持了 OPTN 相关青光眼不是由功能丧失疾病机制引起的可能性。使用这些 Optn 小鼠的进一步研究将阐明参与 NTG 的详细分子途径，并确定可作为青光眼治疗靶点的临床或环境风险因素。
