title: Neuoroprotective efficacies by KUS121, a VCP modulator, on animal models of retinal degeneration.
abstract: 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.
authors: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan.
authors: Tomoko
authors: T
authors: Hasegawa
authors: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan.
authors: Yuki
authors: Y
authors: Muraoka
authors: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan.|Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto university Hospital, Kyoto, 606-8501, Japan.
authors: Hanako Ohashi
authors: HO
authors: Ikeda
authors: Center for Anatomical Studies, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan.
authors: Tatsuaki
authors: T
authors: Tsuruyama
authors: Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, 514-8607, Japan.
authors: Mineo
authors: M
authors: Kondo
authors: Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, 464-8601, Japan.
authors: Hiroko
authors: H
authors: Terasaki
authors: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies &Solution Oriented Research for Science and Technology, Kyoto, 606-8501, Japan.
authors: Akira
authors: A
authors: Kakizuka
authors: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan.
authors: Nagahisa
authors: N
authors: Yoshimura
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D011817:Rabbits; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000074405:Valosin Containing Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse