title: Neuroprotective effects of VCP modulators in mouse models of glaucoma.
abstract: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Nakano
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan; Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 606-8507, Kyoto, Japan.
authors.forename: Hanako Ohashi
authors.initials: HO
authors.lastname: Ikeda
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Muraoka
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan; Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 606-8507, Kyoto, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Iwai
authors.affiliation: Center for Anatomical Studies, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tsuruyama
authors.affiliation: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology, Kyoto, 606-8501, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakano
authors.affiliation: Daito Chemix, Ishibashi-cho Fukui-city Fukui 910-3137, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Fuchigami
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan; Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology, Kyoto, 606-8501, Japan; Daito Chemix, Ishibashi-cho Fukui-city Fukui 910-3137, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shudo
authors.affiliation: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology, Kyoto, 606-8501, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kakizuka
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan; Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 606-8507, Kyoto, Japan.
authors.forename: Nagahisa
authors.initials: N
authors.lastname: Yoshimura
keywords: Cell biology; Neuroscience