Pathophysilogical Mechanism and Treatment Strategies for Leber Congenital Amaurosis
Pathophysilogical Mechanism and Treatment Strategies for Leber Congenital Amaurosis
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DOI：
10.1007/978-1-4614-3209-8_99
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发表时间：
2014-01-01
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影响因子：
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通讯作者：
Zhang, Tao
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文献类型：
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作者：
Fu, Yingbin;Zhang, Tao
类视黄醇异构酶、RPE65 或卵磷脂视黄醇酰基转移酶 (LRAT) 的突变会破坏 11-顺式视网膜循环并导致莱伯先天性黑蒙 (LCA)，这是儿童早期最严重的视网膜营养不良。我们使用Lrat(-/-)（一种LCA小鼠模型）来研究视锥细胞快速变性的机制。我们发现，在大量腹侧/中央视锥细胞退化之前，错误定位的 M-视蛋白被降解，而错误定位的 S-视蛋白在 Lrat(-/-) 视锥细胞中积累。由于小鼠腹侧和中央视网膜比背侧视网膜表达更高水平的 S-视蛋白，因此我们的结果可以解释为什么在 Rpe65(-/-) 和 Lrat(-/-)LCA 模型中，腹侧和中央视锥细胞比背侧视锥细胞退化得更快。此外，人蓝视蛋白和小鼠S视蛋白，但不是小鼠M视蛋白或人红/绿视蛋白，在转染细胞中聚集形成细胞质内含物，这可以解释为什么LCA患者中蓝视锥细胞功能比红/绿视锥细胞功能更早丧失。短波长视蛋白的聚集可能通过 ER 应激途径引起视锥细胞快速变性，如 Lrat(-/-) 视网膜和转染细胞中所证明的那样。基于这一机制，我们设计了一种通过减少ER应激来治疗LCA的新疗法。我们发现全身注射内质网化学伴侣牛磺熊去氧胆酸 (TUDCA) 可有效减轻 Lrat(-/-) 小鼠的内质网应激、防止细胞凋亡并保护视锥细胞。
Mutations in retinoid isomerase, RPE65, or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal recycling and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early childhood. We used Lrat(-/-), a murine model for LCA, to investigate the mechanism of rapid cone degeneration. We found that mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat(-/-)cones before the onset of massive ventral/ central cone degeneration. Since the ventral and central retina expresses higher levels of S-opsin than the dorsal retina in mice, our results may explain why ventral and central cones degenerate more rapidly than dorsal cones in Rpe65(-/-)and Lrat(-/-)LCA models. In addition, human blue opsin and mouse S-opsin, but not mouse M-opsin or human red/ green opsins, aggregated to form cytoplasmic inclusions in transfected cells, which may explain why blue cone function is lost earlier than red/ green-cone function in LCA patients. The aggregation of short-wavelength opsins likely caused rapid cone degenerations through an ER stress pathway as demonstrated in both the Lrat(-/-)retina and transfected cells. Based on this mechanism, we designed a new therapy of LCA by reducing ER stress. We found that systemic injection of an ER chemical chaperone, tauroursodeoxycholic acid (TUDCA), is effective in reducing ER stress, preventing apoptosis, and preserving cones in Lrat(-/-)mice.