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

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

doi:10.1038/srep05970

Hanako Ohashi Ikeda, Yoshinobu Toda + Show 10 more

Open Access

https://doi.org/10.1038/srep05970

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Journal: Scientific Reports	Publication Date: Aug 6, 2014
Citations: 53	License type: CC BY 4.0

Affiliation: Kyoto University, Dainichiseika (Japan)

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.

Highlights

Neuroprotection may prevent or forestall the progression of incurable eye diseases, such as retinitis pigmentosa, one of the major causes of adult blindness
Consistent with this possibility, valosincontaining protein (VCP) mutations were identified that are causative for IBMPFD6, a human hereditary disease with dementia, or for rare cases of familial amyotrophic lateral sclerosis (ALS)[7]
In our search for novel VCP ATPase inhibitors, we found that a naphthalene derivative can inhibit the ATPase activity of VCP with no apparent toxicity at 10 mM on cultured cells

Summary

Introduction

Neuroprotection may prevent or forestall the progression of incurable eye diseases, such as retinitis pigmentosa, one of the major causes of adult blindness. 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 examined their in vivo efficacies in rd[10], 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.

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Conclusion