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HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2020-11-06 , DOI: 10.1038/s41418-020-00653-3
Marijana Samardzija 1 , Andrea Corna 2, 3, 4 , Raquel Gomez-Sintes 5 , Mohamed Ali Jarboui 3 , Angela Armento 3 , Jerome E Roger 6 , Eleni Petridou 3, 7 , Wadood Haq 3 , Francois Paquet-Durand 3 , Eberhart Zrenner 3 , Pedro de la Villa 8 , Günther Zeck 2 , Christian Grimm 1 , Patricia Boya 5 , Marius Ueffing 3 , Dragana Trifunović 3
Affiliation  

Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages.



中文翻译:

HDAC抑制改善视网膜色素变性小鼠视锥细胞存活率

遗传性视网膜疾病(如色素性视网膜炎 (RP))中的视锥细胞死亡会导致高敏锐度和色觉丧失,并最终导致失明。在 RP 中,大量突变扰乱了视杆细胞的结构和功能,而视锥细胞最初不受影响。在疾病的晚期阶段,广泛的视杆细胞损失会通过一种在很大程度上仍然未知的机制引发视锥细胞死亡。在这里,我们显示 RP 动物模型中的继发性锥细胞死亡与组蛋白脱乙酰基 (HDAC) 活性增加有关。在疾病的晚期,当大多数视杆细胞已经退化时,单次玻璃体内注射 HDAC 抑制剂足以在两种受磷酸二酯酶突变影响的 RP 小鼠模型中延迟视锥细胞死亡并支持视锥细胞的长期存活6b基因。此外,幸存的视锥细胞仍然对光敏感,从而改善了视觉功能。受保护锥体的 RNA-seq 分析表明,HDAC 抑制通过调节不同的促生存途径(包括 MAPK、PI3K-Akt 和自噬)启动了多级保护。这项研究提出了一个独特的机会,通过抑制 HDAC 对二次垂死视锥细胞进行靶向药理学保护,并为即使处于晚期疾病阶段的 RP 患者保持视力创造了希望。

更新日期:2020-11-06
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