Department of Genetics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France
Department of Genetics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France.
Cold Spring Harb Perspect Med. 2024 Nov 1;14(11):a041284. doi: 10.1101/cshperspect.a041284.
Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization. Retinitis pigmentosa is a prevalent form of inherited retinal degeneration characterized by initial loss of low-light vision caused by the death of rod photoreceptors. In this disease, rods die as a direct effect of an inherited mutation. Following the loss of rods, cones eventually degenerate, resulting in complete blindness. The progression of vision loss in retinitis pigmentosa suggested that rod photoreceptors were necessary to maintain healthy cones. We identified a protein secreted by rods that functions to promote cone survival, and we named it rod-derived cone viability factor (RdCVF). RdCVF is encoded by an alternative splice product of the nucleoredoxin-like 1 () gene, and RdCVF was found to accelerate the uptake of glucose by cones. Without RdCVF, cones eventually die because of compromised glucose uptake and utilization. The gene also encodes for the thioredoxin RdCVFL, which reduces cysteines in photoreceptor proteins that are oxidized, providing a defense against radical oxygen species. We will review here the main steps of discovering this novel intercellular signaling currently under translation as a broad-spectrum treatment for retinitis pigmentosa.
视觉是由高度专业化的感觉纤毛（称为光感受器外节）捕获光子引发的。由于其脂质和蛋白质组成，外节容易发生光氧化，这要求光感受器具有强大的抗氧化防御能力和高代谢合成率，以每 10 天再生一次外节。这两个过程都需要高水平的葡萄糖摄取和利用。色素性视网膜炎是一种常见的遗传性视网膜变性形式，其特征是最初由于视杆细胞的死亡而导致低光视力丧失。在这种疾病中，视杆细胞是由于遗传突变的直接影响而死亡的。在视杆细胞丧失后，视锥细胞最终退化，导致完全失明。色素性视网膜炎的视力丧失进展表明，视杆细胞对于维持健康的视锥细胞是必要的。我们鉴定了一种由视杆细胞分泌的蛋白，它具有促进视锥细胞存活的功能，我们将其命名为视杆源性视锥细胞生存因子（RdCVF）。RdCVF 是由核还原蛋白样 1（）基因的一种选择性剪接产物编码的，并且 RdCVF 被发现可加速视锥细胞对葡萄糖的摄取。没有 RdCVF，视锥细胞最终会因为葡萄糖摄取和利用受损而死亡。该基因还编码硫氧还蛋白 RdCVFL，它还原被氧化的光感受器蛋白中的半胱氨酸，为对抗活性氧提供防御。在这里，我们将回顾发现这种新型细胞间信号的主要步骤，目前正在作为一种广谱治疗色素性视网膜炎进行翻译。
