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Nat Commun. 2018 Apr 30;9(1):1738. doi: 10.1038/s41467-018-04117-8.

Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration.

Author information

1
Department of Ophthalmology, Duke University School of Medicine, Durham, NC, 27510, USA.
2
Department of Ophthalmology, University of Florida, Gainesville, FL, 32610, USA.
3
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
4
Amgen, One Amgen Center Way, Thousand Oaks, CA, 91320, USA.
5
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27510, USA.
6
Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, 91125, USA.
7
Department of Ophthalmology, Duke University School of Medicine, Durham, NC, 27510, USA. vadim.arshavsky@duke.edu.
8
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27510, USA. vadim.arshavsky@duke.edu.

Abstract

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.

PMID:
29712894
PMCID:
PMC5928105
DOI:
10.1038/s41467-018-04117-8
[Indexed for MEDLINE]
Free PMC Article

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