Department of Cell Biology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Adv Exp Med Biol. 2012;723:191-7. doi: 10.1007/978-1-4614-0631-0_26.
The mechanism of autosomal dominant retinitis pigmentosa (ADRP) caused by the P23H mutation in rhodopsin is tightly associated with misfolded rhodopsin (RHO) which causes endoplasmic reticulum overload (ER stress), activates the unfolded protein response (UPR) and triggers apoptosis. In efforts to create a therapy for ADRP caused by the P23H mutation, we have explored different approaches leading to survival of photoreceptor (PR) cells. The direct approach involves the modulation of the level of wild-type RHO, while the indirect approach involves reprogramming the UPR and increasing the expression of heat shock proteins (HSPs). Taking the direct approach, we found that over-expression of wild-type RHO rescues scotopic ERG responses partially. However, greater therapeutic effects were obtained by manipulation of the UPR in P23H RHO rat PRs treated with the endoplasmic reticulum protein BiP/Grp78. study revealed that the pro-survival effect of Bip gene was not associated with its function as a molecular chaperone, but rather with its regulation of the UPR. Another indirect approach was the over-expression of the Hsf-1 gene, a transcriptional regulator of the heat shock response. AAV-delivery of Hsf-1 resulted in an increase of scotopic ERG amplitudes by over 35%. Taken together these data suggest viable therapeutic treatments for ADRP.
常染色体显性遗传视网膜色素变性（ADRP）的发病机制与视紫红质（RHO）的错误折叠紧密相关，错误折叠的 RHO 会导致内质网过载（ER 应激），激活未折叠蛋白反应（UPR）并引发细胞凋亡。为了研发针对 P23H 突变引起的 ADRP 的治疗方法，我们探索了不同的方法以实现对感光细胞（PR）的保护。直接方法涉及调节野生型 RHO 的水平，而间接方法则涉及重编程 UPR 并增加热休克蛋白（HSPs）的表达。在直接方法中，我们发现过表达野生型 RHO 可部分挽救暗视 ERG 反应。然而，通过操纵 P23H RHO 大鼠 PR 中的 UPR 并使用内质网蛋白 BiP/Grp78 处理，可获得更大的治疗效果。该研究表明，Bip 基因的促生存作用与其作为分子伴侣的功能无关，而与其对 UPR 的调节有关。另一种间接方法是过表达热休克反应的转录调节因子 Hsf-1 基因。AAV 递送 Hsf-1 可使暗视 ERG 幅度增加超过 35%。这些数据表明，针对 ADRP 存在可行的治疗方法。
