Neuroprotective effects of VCP modulators in mouse models of glaucoma
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 reduc...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2016-04-01
|
Series: | Heliyon |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844015303832 |
id |
doaj-baf9c64971774702b029eb17d3b9aea3 |
---|---|
record_format |
Article |
spelling |
doaj-baf9c64971774702b029eb17d3b9aea32020-11-24T22:25:58ZengElsevierHeliyon2405-84402016-04-012410.1016/j.heliyon.2016.e00096Neuroprotective effects of VCP modulators in mouse models of glaucomaNoriko Nakano0Hanako Ohashi Ikeda1Tomoko Hasegawa2Yuki Muraoka3Sachiko Iwai4Tatsuaki Tsuruyama5Masaki Nakano6Tomohiro Fuchigami7Toshiyuki Shudo8Akira Kakizuka9Nagahisa Yoshimura10Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, JapanDepartment of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, JapanDepartment of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, JapanDepartment of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, JapanDepartment of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, JapanCenter for Anatomical Studies, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, JapanLaboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology, Kyoto, 606-8501, JapanDaito Chemix, Ishibashi-cho Fukui-city Fukui 910-3137, JapanDepartment of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, JapanLaboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology, Kyoto, 606-8501, JapanDepartment of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, JapanGlaucoma 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.http://www.sciencedirect.com/science/article/pii/S2405844015303832Cell biologyNeuroscience |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Noriko Nakano Hanako Ohashi Ikeda Tomoko Hasegawa Yuki Muraoka Sachiko Iwai Tatsuaki Tsuruyama Masaki Nakano Tomohiro Fuchigami Toshiyuki Shudo Akira Kakizuka Nagahisa Yoshimura |
spellingShingle |
Noriko Nakano Hanako Ohashi Ikeda Tomoko Hasegawa Yuki Muraoka Sachiko Iwai Tatsuaki Tsuruyama Masaki Nakano Tomohiro Fuchigami Toshiyuki Shudo Akira Kakizuka Nagahisa Yoshimura Neuroprotective effects of VCP modulators in mouse models of glaucoma Heliyon Cell biology Neuroscience |
author_facet |
Noriko Nakano Hanako Ohashi Ikeda Tomoko Hasegawa Yuki Muraoka Sachiko Iwai Tatsuaki Tsuruyama Masaki Nakano Tomohiro Fuchigami Toshiyuki Shudo Akira Kakizuka Nagahisa Yoshimura |
author_sort |
Noriko Nakano |
title |
Neuroprotective effects of VCP modulators in mouse models of glaucoma |
title_short |
Neuroprotective effects of VCP modulators in mouse models of glaucoma |
title_full |
Neuroprotective effects of VCP modulators in mouse models of glaucoma |
title_fullStr |
Neuroprotective effects of VCP modulators in mouse models of glaucoma |
title_full_unstemmed |
Neuroprotective effects of VCP modulators in mouse models of glaucoma |
title_sort |
neuroprotective effects of vcp modulators in mouse models of glaucoma |
publisher |
Elsevier |
series |
Heliyon |
issn |
2405-8440 |
publishDate |
2016-04-01 |
description |
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. |
topic |
Cell biology Neuroscience |
url |
http://www.sciencedirect.com/science/article/pii/S2405844015303832 |
work_keys_str_mv |
AT norikonakano neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT hanakoohashiikeda neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT tomokohasegawa neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT yukimuraoka neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT sachikoiwai neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT tatsuakitsuruyama neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT masakinakano neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT tomohirofuchigami neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT toshiyukishudo neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT akirakakizuka neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma AT nagahisayoshimura neuroprotectiveeffectsofvcpmodulatorsinmousemodelsofglaucoma |
_version_ |
1725755352004165632 |