title: Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa.
abstract: Neuroprotection may prevent or forestall the progression of incurable eye diseases, such as retinitis pigmentosa, one of the major causes of adult blindness. Decreased cellular ATP levels may contribute to the pathology of this eye disease and other neurodegenerative diseases. Here we describe small compounds (Kyoto University Substances, KUSs) that were developed to inhibit the ATPase activity of VCP (valosin-containing protein), the most abundant soluble ATPase in the cell. Surprisingly, KUSs did not significantly impair reported cellular functions of VCP but nonetheless suppressed the VCP-dependent decrease of cellular ATP levels. Moreover, KUSs, as well as exogenous ATP or ATP-producing compounds, e.g. methylpyruvate, suppressed endoplasmic reticulum stress, and demonstrably protected various types of cultured cells from death, including several types of retinal neuronal cells. We then examined their in vivo efficacies in rd10, a mouse model of retinitis pigmentosa. KUSs prevented photoreceptor cell death and preserved visual function. These results reveal an unexpected, crucial role of ATP consumption by VCP in determining cell fate in this pathological context, and point to a promising new neuroprotective strategy for currently incurable retinitis pigmentosa.
authors.affiliation: 1] Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan [2] Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan.
authors.forename: Hanako Ohashi
authors.initials: HO
authors.lastname: Ikeda
authors.affiliation: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Sasaoka
authors.affiliation: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Koike
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8501, 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 606-8501, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Muraoka
authors.affiliation: Center for Anatomical Studies, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Toda
authors.affiliation: Daito Chemix, Ishibashi-cho Fukui-city Fukui 910-3137, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Fuchigami
authors.affiliation: 1] Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan [2] Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan [3] 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, Kyoto 606-8501, Japan.
authors.forename: Ayana
authors.initials: A
authors.lastname: Iwata
authors.affiliation: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Hori
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Nagahisa
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kakizuka
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000819:agonists / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015870:Gene Expression; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016716:PC12 Cells; D011773:Pyruvates / Q000494:pharmacology; D051381:Rats; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011773:Pyruvates; D054852:Small Molecule Libraries; C104813:methyl pyruvate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; C000614180:Vcp protein, rat
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