Department of Neuroscience, Rockefeller Neuroscience Institute, 33 Medical Centre Drive, West Virginia University, Morgantown, WV, 26506, USA; Department of Ophthalmology and Visual Sciences, One Medical Center Drive, ERMA 2nd Floor, West Virginia University, Morgantown, WV, 26505-9193, USA.
Department of Ophthalmology and Visual Sciences, One Medical Center Drive, ERMA 2nd Floor, West Virginia University, Morgantown, WV, 26505-9193, USA.
Exp Eye Res. 2024 Sep;246:110016. doi: 10.1016/j.exer.2024.110016. Epub 2024 Aug 5.
Progressive Rod-Cone Degeneration (PRCD) is an integral membrane protein found in photoreceptor outer segment (OS) disc membranes and its function remains unknown. Mutations in Prcd are implicated in Retinitis pigmentosa (RP) in humans and multiple dog breeds. PRCD-deficient models exhibit decreased levels of cholesterol in the plasma. However, potential changes in the retinal cholesterol remain unexplored. In addition, impaired phagocytosis observed in these animal models points to potential deficits in the retinal pigment epithelium (RPE). Here, using a Prcd murine model we investigated the alterations in the retinal cholesterol levels and impairments in the structural and functional integrity of the RPE. Lipidomic and immunohistochemical analyses show a 5-fold increase in the levels of cholesteryl esters (C.Es) and lipid deposits in the PRCD-deficient retina, respectively, indicating alterations in total retinal cholesterol. Furthermore, the RPE of Prcd mice exhibit a 1.7-fold increase in the expression of lipid transporter gene ATP-binding cassette transporter A1 (Abca1). Longitudinal fundus and spectral domain optical coherence tomography (SD-OCT) examinations showed focal lesions and RPE hyperreflectivity. Strikingly, the RPE of Prcd mice exhibited age-related pathological features such as lipofuscin accumulation, Bruch's membrane (BrM) deposits and drusenoid focal deposits, mirroring an Age-related Macular Degeneration (AMD)-like phenotype. We propose that the extensive lipofuscin accumulation likely impairs lysosomal function, leading to the defective phagocytosis observed in Prcd mice. Our findings support the dysregulation of retinal cholesterol homeostasis in the absence of PRCD. Further, we demonstrate that progressive photoreceptor degeneration in Prcd mice is accompanied by progressive structural and functional deficits in the RPE, which likely exacerbates vision loss over time.
进行性视锥-视杆细胞营养不良（PRCD）是一种存在于光感受器外段（OS）盘膜中的完整膜蛋白，其功能尚不清楚。Prcd 突变与人类和多种犬种的色素性视网膜炎（RP）有关。PRCD 缺陷模型表现出血浆胆固醇水平降低。然而，视网膜胆固醇的潜在变化尚未得到探索。此外，这些动物模型中观察到的吞噬作用受损表明视网膜色素上皮（RPE）可能存在潜在缺陷。在这里，我们使用 Prcd 小鼠模型研究了视网膜胆固醇水平的变化以及 RPE 的结构和功能完整性的损伤。脂质组学和免疫组织化学分析分别显示 Prcd 缺陷型视网膜中胆固醇酯（C.Es）水平增加了 5 倍，脂质沉积增加了 5 倍，表明总视网膜胆固醇发生了变化。此外，Prcd 小鼠的 RPE 中脂质转运蛋白基因 ATP 结合盒转运蛋白 A1（Abca1）的表达增加了 1.7 倍。纵向眼底和光谱域光学相干断层扫描（SD-OCT）检查显示局灶性病变和 RPE 高反射性。引人注目的是，Prcd 小鼠的 RPE 表现出与年龄相关的病理性特征，如脂褐素积累、Bruch 膜（BrM）沉积和类 drusen 样局灶性沉积，反映出与年龄相关的黄斑变性（AMD）样表型。我们提出，大量脂褐素的积累可能会损害溶酶体功能，导致 Prcd 小鼠中观察到的吞噬作用缺陷。我们的研究结果支持在缺乏 PRCD 的情况下视网膜胆固醇动态平衡的失调。此外，我们证明 Prcd 小鼠进行性光感受器变性伴随着 RPE 的进行性结构和功能缺陷，这可能随着时间的推移导致视力丧失加剧。
