Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration

Inherited retinal disorders (IRDs) result in severe visual impairments in children and adults. A challenge in the field of retinal degenerations is identifying mechanisms of photoreceptor cell death related to specific genetic mutations. Mutations in the gene TULP1 have been associated with two forms of IRDs, early-onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). TULP1 is a cytoplasmic, membrane-associated protein shown to be involved in transportation of newly synthesized proteins destined for the outer segment compartment of photoreceptor cells; however, how mutant TULP1 causes cell death is not understood. In this study, we provide evidence that common missense mutations in TULP1 express as misfolded protein products that accumulate within the endoplasmic reticulum (ER) causing prolonged ER stress. In an effort to maintain protein homeostasis, photoreceptor cells then activate the unfolded protein response (UPR) complex. Our results indicate that the two major apoptotic arms of the UPR pathway, PERK and IRE1, are activated. Additionally, we show that retinas expressing mutant TULP1 significantly upregulate the expression of CHOP, a UPR signaling protein promoting apoptosis, and undergo photoreceptor cell death. Our study demonstrates that the ER-UPR, a known mechanism of apoptosis secondary to an overwhelming accumulation of misfolded protein, is involved in photoreceptor degeneration caused by missense mutations in TULP1. These observations suggest that modulating the UPR pathways might be a strategy for therapeutic intervention.

遗传性视网膜疾病（Inherited retinal disorders, IRDs）会导致儿童与成人出现严重视力障碍。视网膜变性研究领域的一大挑战，在于明确与特定基因突变相关的感光细胞死亡机制。TULP1基因的突变已被证实与两种遗传性视网膜疾病相关：早发性视网膜色素变性（retinitis pigmentosa, RP）以及莱伯先天性黑蒙（Leber congenital amaurosis, LCA）。TULP1是一种胞质型膜结合蛋白，此前研究表明其参与靶向感光细胞外节区的新合成蛋白质运输，但突变型TULP1引发细胞死亡的具体机制尚未阐明。本研究证实，TULP1常见错义突变会表达为错误折叠的蛋白质产物，此类产物会在内质网（endoplasmic reticulum, ER）中蓄积并引发持续性内质网应激。为维持蛋白质稳态，感光细胞会激活未折叠蛋白反应（unfolded protein response, UPR）通路。研究结果显示，UPR通路的两大主要凋亡分支——PERK与IRE1——被激活。此外，表达突变型TULP1的视网膜会显著上调促凋亡UPR信号蛋白CHOP的表达，并最终引发感光细胞死亡。本研究表明，内质网未折叠蛋白反应（ER-UPR）——一种已知的、由错误折叠蛋白质过度蓄积引发的细胞凋亡机制——参与了TULP1错义突变所致的感光细胞变性。上述发现提示，调控UPR通路或可成为该疾病的治疗干预策略。