恢复杆衍生代谢和氧化还原信号以预防失明。

IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor perspectives in medicine Pub Date : 2024-11-01 DOI:10.1101/cshperspect.a041284
Emmanuelle Clérin, Najate Aït-Ali, José-Alain Sahel, Thierry Léveillard
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引用次数: 0

摘要

视觉是通过在被称为光感受器外段的高度专业化的感觉纤毛中捕获光子来启动的。由于其脂质和蛋白质组成,外层节段容易发生光氧化,需要光感受器具有强大的抗氧化防御能力和高代谢合成率,才能每10天再生一次外层节段。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,其特征是由杆状光感受器死亡引起的初始微光视力丧失。在这种疾病中,杆状病毒的死亡是遗传突变的直接影响。失去视杆后,视锥最终退化,导致完全失明。色素性视网膜炎视力下降的进展表明,杆状光感受器是维持视锥健康所必需的。我们鉴定了一种由杆状细胞分泌的蛋白质,该蛋白质具有促进锥体存活的功能,并将其命名为杆状细胞衍生的锥体活力因子(RdCVF)。RdCVF由核氧还蛋白样1(NXNL1)基因的另一种剪接产物编码,发现RdCVF可加速视锥对葡萄糖的摄取。如果没有RdCVF,视锥细胞最终会因葡萄糖摄取和利用受损而死亡。NXNL1基因还编码硫氧还蛋白RdCVFL,它减少被氧化的光感受器蛋白中的半胱氨酸,提供对自由基氧物种的防御。我们将在这里回顾发现这种新的细胞间信号传导的主要步骤,目前正被翻译为色素性视网膜炎的广谱治疗方法。
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Restoration of Rod-Derived Metabolic and Redox Signaling to Prevent Blindness.

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 (NXNL1) 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 NXNL1 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.

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来源期刊
Cold Spring Harbor perspectives in medicine
Cold Spring Harbor perspectives in medicine MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
14.30
自引率
1.90%
发文量
44
审稿时长
4-8 weeks
期刊介绍: Cold Spring Harbor Perspectives in Medicine is a monthly online publication comprising reviews on different aspects of a variety of diseases, covering everything from the molecular and cellular bases of disease to translational medicine and new therapeutic strategies. Cold Spring Harbor Perspectives in Medicine is thus unmatched in its depth of coverage and represents an essential source where readers can find informed surveys and critical discussion of advances in molecular medicine.
期刊最新文献
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