Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa

Ikeda, Hanako Ohashi; Sasaoka, Norio; Koike, Masayuki; Nakano, Nobuhiko; Muraoka, Yuki; Toda, Yoshinobu; Fuchigami, Tomohiro; Shudo, Toshiyuki; Iwata, Ayana; Hori, Seiji; Yoshimura, Nagahisa; Kakizuka, Akira

doi:10.1038/srep05970

Cited by 53 publications

(101 citation statements)

References 34 publications

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“…In our previous studies, KUS121 showed significant neuroprotective effects in rd10 mice, rd12 mice, and mutated rhodopsin transgenic rabbits, which are models of retinitis pigmentosa1719. Similar results were obtained using three different mouse models of glaucoma but without observable side effects18.…”

Section: Discussionsupporting

confidence: 68%

KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress

Hata

Ikeda

Kikkawa

et al. 2017

Sci Rep

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Ischemic neural damages cause several devastating diseases, including brain stroke and ischemic retinopathies, and endoplasmic reticulum (ER) stress has been proposed to be the underlying mechanism of the neuronal cell death of these conditions. We previously synthesized Kyoto University substances (KUSs) as modulators of valosin-containing protein (VCP); KUSs inhibit VCP ATPase activity and protect cells from different cell death-inducing insults. Here, we examined the efficacy of KUS121 in a rat model of retinal ischemic injury. Systemic administration of KUS121 to rats with ischemic retinal injury significantly suppressed inner retinal thinning and death of retinal ganglion and amacrine cells, with a significant functional maintenance of visual functions, as judged by electroretinography. Furthermore, intravitreal injection of KUS121, which is the clinically preferred route of drug administration for retinal diseases, appeared to show an equal or better neuroprotective efficacy in the ischemic retina compared with systemic administration. Indeed, induction of the ER stress marker C/EBP homologous protein (CHOP) after the ischemic insult was significantly suppressed by KUS121 administration. Our study suggests VCP modulation by KUS as a promising novel therapeutic strategy for ischemic neuronal diseases.

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Section: Discussionsupporting

confidence: 68%

KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress

Hata

Ikeda

Kikkawa

et al. 2017

Sci Rep

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“…Because many proteins require ATP, a reduction of ATP levels would contribute to a functional decline in affected cells or organs in the early stages of the disease. Reducing ATP consumption by way of KUSs and/or enhancing ATP generation by yet-unknown compounds would be a novel strategy to retard these processes and thus to prevent or retard the progression of clinical manifestations [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…4h ) showed that KUS treatments had the potential to prevent or delay the disease progression. When examined by electron microscopy, the outer segment of the control rd10 mouse retina was mostly disarranged at the age of 21 days, whereas that of the KUS-treated rd10 mouse retina was regularly arranged [ 22 ].…”

Section: Kuss Mitigated Pathologies Of Rd10 a Mouse Model Of Retinitmentioning

confidence: 99%

VCP, a Major ATPase in the Cells, as a Novel Drug Target for Currently Incurable Disorders

Kakizuka

2015

Innovative Medicine

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Neuroprotection would be a novel therapeutic strategy for the prevention or retardation of clinical manifestations of currently incurable eye diseases as well as neurodegenerative diseases. A decrease in cellular ATP levels may contribute to the pathologies of these diseases; therefore, stabilization of ATP levels may retard the disease progression. We created novel small compounds (Kyoto University Substances, KUSs) to inhibit the ATPase activity of VCP (valosin-containing protein), the most abundant soluble ATPase in the cell. KUSs did not apparently impair the reported cellular VCP functions. Nevertheless, they signifi cantly suppressed the VCP-dependent decrease of cellular ATP levels. Moreover, KUSs as well as exogenous ATP or ATP-producing compounds suppressed endoplasmic reticulum (ER) stress, and indeed protected various types of cultured cells from cell deathinducing insults. We then examined the effi cacies of KUSs in rd10, a mouse model of retinitis pigmentosa. KUSs not only prevented photoreceptor cell death but also preserved visual function. These results reveal an unexpected, crucial role of ATP consumption by VCP for the determination of cell fate in the pathological context, and point to a promising new neuroprotective strategy for currently incurable eye and neurodegenerative diseases.

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“…Although SD-OCT is a noninvasive technology that allows us to investigate the morphological characteristics of various retinal diseases [20,21], it is impossible to directly evaluate the pathological features. In contrast, animal models associated with known gene mutations provide strong evidence that facilitate our understanding of the relationship between the SD-OCT findings and the pathological background [22][23][24][25][26][27][28][29][30][31][32]. However, to our knowledge, no study has assessed the relationship between SD-OCT findings and the origin of the structural changes in Rdh5 -/mice.…”

Section: Introductionmentioning

confidence: 99%

A spectral-domain optical coherence tomographic analysis of Rdh5-/- mice retina

et al. 2020

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To investigate the longitudinal findings of spectral-domain optical coherence tomography (SD-OCT) in relation to the morphologic features in Rdh5 knockout (Rdh5-/-) mice. Materials and methods The mouse retina was segmented into four layers; the inner retinal (A), outer plexiform and outer nuclear (B), rod/cone (C), and retinal pigment epithelium (RPE)/choroid (D) layers. The thickness of each retinal layer of Rdh5-/mice was longitudinally and quantitatively measured at six time points from postnatal months (PM) 1 to PM6 using SD-OCT. Age-matched C57BL/6J mice were employed as wild-type controls. The data were statistically compared using Student's t-test. The fundus appearance was assessed, histologic and ultrastructural examinations were performed in both groups. Results Layers A and B were significantly thinner in the Rdh5-/mice than in the wild-type C57BL/6J mice during the observation periods. Layers C and D became thinner in the Rdh5-/mice than in the wild-type mice after PM6. Although no abnormalities corresponding to whitish fundus dots were detected by SD-OCT or histologic examinations, the intracellular accumulation of low-density vacuoles was noted in the RPE of the Rdh5-/mice by electron microscopy. The photoreceptor nuclei appeared less dense in the Rdh5-/mice than in the wildtype mice. Discussion The results from the present study suggest that although it is difficult to detect qualitative abnormalities, SD-OCT can detect quantitative changes in photoreceptors even in the early stage of retinal degeneration induced by the Rdh5 gene mutation in mice.

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Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa

Cited by 53 publications

References 34 publications

KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress

KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress

VCP, a Major ATPase in the Cells, as a Novel Drug Target for Currently Incurable Disorders

A spectral-domain optical coherence tomographic analysis of Rdh5-/- mice retina

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