Neuoroprotective efficacies by KUS121, a VCP modulator, on animal models of retinal degeneration.
Neuoroprotective efficacies by KUS121, a VCP modulator, on animal models of retinal degeneration.
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DOI：
10.1038/srep31184
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发表时间：
2016-08-09
影响因子：
4.6
通讯作者：
Yoshimura N
中科院分区：
文献类型：
--
作者：
Hasegawa T;Muraoka Y;Ikeda HO;Tsuruyama T;Kondo M;Terasaki H;Kakizuka A;Yoshimura N
视网膜色素变性(RP)是成人致盲的主要原因之一，目前还没有确定的治疗方法。我们已经证明，含有Valosin的蛋白(VCP)调节剂京都大学物质(KUSS)通过抑制VCP的ATPase来改善异常低的ATP水平，从而保护包括视网膜神经元在内的几种类型的细胞免受细胞死亡诱导的损伤。在这项研究中，我们发现VCP调节剂之一KUS121在RD12小鼠和视紫红质(Pro347Leu)突变的RP兔两种视网膜变性动物模型上，从形态和功能上都有效地保护了光感受器。在RD12小鼠中，KUS121抑制光感受器的丢失，不仅是视杆细胞，也包括视锥细胞，以及视觉功能的恶化。即使在疾病的后期开始用药，也存在显著的保护作用。在RP兔中，KUS121抑制外核层变薄，并维持视功能。在KUS121处理的视网膜中，内质网应激受到明显的抑制，雷帕霉素的哺乳动物靶点被激活，疾病相关的细胞凋亡受到抑制。KUS121保护光感受器的能力，特别是视锥细胞，甚至在疾病的晚期，可能有助于保护RP患者的中心视力，这对视力质量是重要的。
Retinitis pigmentosa (RP) is one of the leading causes of adult blindness and has no established therapy. We have shown that valosin-containing protein (VCP) modulators, Kyoto University Substances (KUSs), ameliorated abnormally low ATP levels by inhibiting the ATPase of VCP, thereby protected several types of cells, including retinal neurons, from cell death-inducing insults. In this study, we found that KUS121, one of the VCP modulators, effectively protects photoreceptors both morphologically and functionally, in two animal models of retinal degeneration, rd12 mice and RP rabbits with a rhodopsin (Pro347Leu) mutation. In rd12 mice, KUS121 suppressed the loss of photoreceptors, not only rods but also cones, as well as the visual function deterioration. Significant protective effects existed even when the medication was started in later stages of the disease. In RP rabbits, KUS121 suppressed thinning of the outer nuclear layer and maintained visual function. In the retinas treated with KUS121, suppression of endoplasmic reticulum stress, activation of mammalian target of rapamycin and suppression of disease-associated apoptosis were evident. The ability of KUS121 to protect photoreceptors, especially cones, even in later stages of the disease may contribute to the preservation of central vision in RP patients, which is important for quality of vision.