Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration

Ekaterina S. Lobanova, Stella Finkelstein, Jing Li, Amanda M. Travis, Ying Hao, Mikael Klingeborn, Nikolai P. Skiba, Raymond J. Deshaies and Vadim Y. Arshavsky ()
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Ekaterina S. Lobanova: Duke University School of Medicine
Stella Finkelstein: Duke University School of Medicine
Jing Li: California Institute of Technology
Amanda M. Travis: Duke University School of Medicine
Ying Hao: Duke University School of Medicine
Mikael Klingeborn: Duke University School of Medicine
Nikolai P. Skiba: Duke University School of Medicine
Raymond J. Deshaies: California Institute of Technology
Vadim Y. Arshavsky: Duke University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04117-8

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