Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-06, Vol.110 (24), p.9986-9991
• Main Authors: Lobanova, Ekaterina S., Finkelstein, Stella, Skiba, Nikolai P., Arshavsky, Vadim Y.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Biological Sciences; Blotting, Western; Chaperonins; Chromatography; Eye and associated structures. Visual pathways and centers. Vision; Fluorescence; Fundamental and applied biological sciences. Psychology; Genes; Genetic mutation; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Medical treatment; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pathology; Photoreceptors; Proteasome Endopeptidase Complex - metabolism; Protein Subunits - genetics; Protein Subunits - metabolism; Proteins; Retina; Retina - metabolism; Retina - pathology; Retinal degeneration; Retinal Degeneration - genetics; Retinal Degeneration - metabolism; Retinal Rod Photoreceptor Cells - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Stress, Physiological; Transducin - genetics; Transducin - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1305521110

Inherited retinal degenerations, caused by mutations in over 100 individual genes, affect approximately 2 million people worldwide. Many of the underlying mutations cause protein misfolding or mistargeting in affected photoreceptors. This places an increased burden on the protein folding and degradation machinery, which may trigger cell death. We analyzed how these cellular functions are affected in degenerating rods of the transducin γ-subunit (Gγ ₁) knockout mouse. These rods produce large amounts of transducin β-subunit (Gβ ₁), which cannot fold without Gγ ₁ and undergoes intracellular proteolysis instead of forming a transducin βγ-subunit complex. Our data revealed that the most critical pathobiological factor leading to photoreceptor cell death in these animals is insufficient capacity of proteasomes to process abnormally large amounts of misfolded protein. A decrease in the Gβ ₁ production in Gγ ₁ knockout rods resulted in a significant reduction in proteasomal overload and caused a striking reversal of photoreceptor degeneration. We further demonstrated that a similar proteasomal overload takes place in photoreceptors of other mutant mice where retinal degeneration has been ascribed to protein mistargeting or misfolding, but not in mice whose photoreceptor degenerate as a result of abnormal phototransduction. These results establish the prominence of proteasomal insufficiency across multiple degenerative diseases of the retina, thereby positioning proteasomes as a promising therapeutic target for treating these debilitating conditions.