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Updated: Apr 26, 2026
Vibratome Sectioning Mouse Retina to Prepare Photoreceptor Cultures
Published on: December 22, 2014
Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa
Hanako Ohashi Ikeda1, Norio Sasaoka2, Masaaki Koike2
11] 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.
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.
Insights
New compounds (KUSs) inhibit valosin-containing protein (VCP) ATPase activity, preventing cell death and preserving vision in retinitis pigmentosa models. This offers a promising neuroprotective strategy for incurable eye diseases.
Area of Science:
- Neuroscience
- Ophthalmology
- Biochemistry
Background:
- Retinitis pigmentosa is a leading cause of adult blindness.
- Decreased cellular ATP levels contribute to neurodegenerative diseases, including retinitis pigmentosa.
- Valosin-containing protein (VCP) is the most abundant soluble ATPase in cells.
Purpose of the Study:
- To develop novel small compounds (KUSs) targeting VCP ATPase activity for neuroprotection.
- To investigate the role of VCP-dependent ATP consumption in cell fate.
- To evaluate the therapeutic potential of KUSs in retinitis pigmentosa models.
Main Methods:
- Synthesis and characterization of small compounds (KUSs) inhibiting VCP ATPase.
- Assessment of KUS effects on cellular ATP levels and endoplasmic reticulum stress.
- In vitro testing on various cell types, including retinal neuronal cells.
- In vivo efficacy studies in the rd10 mouse model of retinitis pigmentosa.
Main Results:
- KUSs inhibited VCP ATPase activity without impairing VCP's known cellular functions.
- KUSs suppressed VCP-dependent ATP depletion and endoplasmic reticulum stress.
- KUSs protected cultured cells, including retinal neurons, from death.
- In vivo, KUSs prevented photoreceptor cell death and preserved visual function in rd10 mice.
Conclusions:
- VCP's ATP consumption plays a critical role in cell fate in pathological conditions like retinitis pigmentosa.
- KUSs represent a novel neuroprotective strategy for retinitis pigmentosa.
- Targeting VCP ATPase activity offers a promising therapeutic avenue for currently incurable neurodegenerative eye diseases.
