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Published April 30, 2018 | Published + Supplemental Material
Journal Article Open

Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration


Inherited retinal degenerations, affecting more than 2 million people worldwide, are caused by mutations in over 200 genes. This suggests that the most efficient therapeutic strategies would be mutation independent, i.e., targeting common pathological conditions arising from many disease-causing mutations. Previous studies revealed that one such condition is an insufficiency of the ubiquitin–proteasome system to process misfolded or mistargeted proteins in affected photoreceptor cells. We now report that retinal degeneration in mice can be significantly delayed by increasing photoreceptor proteasomal activity. The largest effect is observed upon overexpression of the 11S proteasome cap subunit, PA28α, which enhanced ubiquitin-independent protein degradation in photoreceptors. Applying this strategy to mice bearing one copy of the P23H rhodopsin mutant, a mutation frequently encountered in human patients, quadruples the number of surviving photoreceptors in the inferior retina of 6-month-old mice. This striking therapeutic effect demonstrates that proteasomes are an attractive target for fighting inherited blindness.

Additional Information

© 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received: 23 June 2017; Accepted: 04 April 2018; Published online: 30 April 2018. This work was supported by the National Institutes of Health grants EY022959 (V.Y.A.), EY05722 (V.Y.A.), an Unrestricted Award (Duke University) and a Nelson Trust Award (V.Y.A.) from Research to Prevent Blindness Inc., and grant from the Knights Templar Eye Foundation (E.S.L.). R.J.D. was an Investigator of, and this work was supported in part by, the Howard Hughes Medical Institute. J.L. was also supported in part by a grant from Amgen. Author Contributions: E.S.L., S.F., J.L., A.M.T., R.J.D., and V.Y.A. conceived and designed the experiments. E.S.L, S.F., J.L., A.M.T., Y.H., M.K., and N.P.S. performed the experiments. E.S.L., S.F., J.L., A.M.T., M.K., N.P.S., R.J.D., and V.Y.A. analyzed the data. E.S.L. and V.Y.A. wrote the manuscript. All authors edited the manuscript. The authors declare no competing interests. Data availability: All relevant data are available on reasonable request from the authors.

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Supplemental Material - 41467_2018_4117_MOESM1_ESM.pdf


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