期刊
HELIYON
卷 2, 期 4, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.heliyon.2016.e00096
关键词
Cell biology; Neuroscience
资金
- Astellas Foundation for Research on Metabolic Disorders
- Japan Foundation for Applied Enzymology
- Uehara Memorial Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- YOKOYAMA Foundation for Clinical Pharmacology [YRY1308]
- Japan Intractable Diseases Research Foundation
- Japan Research Foundation for Clinical Pharmacology
- ONO Medical Research Foundation
- Takeda Science Foundation
- Japan National Society for the Prevention of Blindness [24791850]
- SORST of JST
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Ministry of Health, Labour and Welfare of Japan
- Innovative Techno-Hub for Integrated Medical Bio-Imaging of the Project for Developing Innovation Systems from the Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Grants-in-Aid for Scientific Research [15K15633, 24791850, 15H01181] Funding Source: KAKEN
Glaucoma is a major cause of adult blindness due to gradual death of retinal ganglion cells. Currently, no therapeutics are available for the protection of these cells from the cell death. We have recently succeeded in synthesizing novel compounds, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption by specifically inhibiting the ATPase activities of VCP, a major ATPase in the cell, and we have shown that KUSs could mitigate the disease progression of rd10, a mouse model of retinitis pigmentosa, without any apparent side effects. Here we show that KUSs (e.g. KUS121 and KUS187) can prevent antimycin- and oligomycin-induced ATP depletion, endoplasmic reticulum (ER) stress, and cell death in neuronally differentiated PC12 cells. Furthermore, KUSs manifest significant efficacies on several mouse models of glaucoma. KUS administration prevented or mitigated ER stress and subsequent apoptotic cell death of retinal ganglion cells in an acute injury mouse model of retinal ganglion cell loss, which was induced with N-methyl-D-aspartate. In a mouse model of glaucoma with high intraocular pressure, KUSs prevented the typical glaucoma pathologies, i.e. enlargement of optic disc cupping and thinning of the retinal nerve fiber layer. KUSs also preserved visual functions in GLAST knockout mice, a mouse model for chronic retinal ganglion cell loss. We propose ATP maintenance via inhibition of ATPase activities of VCP as a promising new neuroprotective strategy for currently incurable eye diseases, such as glaucoma.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据