Departments of Genetics and Ophthalmology, Blavatnik Institute, Harvard Medical School, Boston, United States.
Lingang Laboratory, Shanghai, China.
Elife. 2024 May 10;12:RP90749. doi: 10.7554/eLife.90749.
Retinitis pigmentosa (RP) is an inherited retinal disease in which there is a loss of cone-mediated daylight vision. As there are >100 disease genes, our goal is to preserve cone vision in a disease gene-agnostic manner. Previously we showed that overexpressing TXNIP, an α-arrestin protein, prolonged cone vision in RP mouse models, using an AAV to express it only in cones. Here, we expressed different alleles of in the retinal pigmented epithelium (RPE), a support layer for cones. Our goal was to learn more of TXNIP's structure-function relationships for cone survival, as well as determine the optimal cell type expression pattern for cone survival. The C-terminal half of TXNIP was found to be sufficient to remove GLUT1 from the cell surface, and improved RP cone survival, when expressed in the RPE, but not in cones. Knock-down of HSP90AB1, a TXNIP-interactor which regulates metabolism, improved the survival of cones alone and was additive for cone survival when combined with TXNIP. From these and other results, it is likely that TXNIP interacts with several proteins in the RPE to indirectly support cone survival, with some of these interactions different from those that lead to cone survival when expressed only in cones.
色素性视网膜炎（RP）是一种遗传性视网膜疾病，其中存在视锥细胞介导的日光视觉丧失。由于有>100 种疾病基因，我们的目标是以疾病基因不可知的方式保留视锥细胞的视力。以前我们表明，通过在视锥细胞中仅表达 TXNIP（一种α-抑制蛋白），可以延长 RP 小鼠模型中的视锥细胞视力，使用 AAV 进行表达。在这里，我们在视网膜色素上皮（RPE）中表达了 的不同等位基因，这是视锥细胞的支持层。我们的目标是更多地了解 TXNIP 对视锥细胞存活的结构-功能关系，并确定用于视锥细胞存活的最佳细胞类型表达模式。发现 TXNIP 的 C 端半胱氨酸能够将 GLUT1 从细胞表面去除，并改善 RPE 中的视锥细胞存活，但在视锥细胞中则不然。HSP90AB1 的敲低，一种调节代谢的 TXNIP 相互作用蛋白，单独改善了视锥细胞的存活，并且与 TXNIP 联合使用时对视锥细胞的存活具有累加作用。根据这些和其他结果，很可能 TXNIP 在 RPE 中与几种蛋白质相互作用，以间接支持视锥细胞的存活，其中一些相互作用与仅在视锥细胞中表达时导致视锥细胞存活的相互作用不同。
