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

Journal Article (Journal Article)

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 (Gγ1) knockout mouse. These rods produce large amounts of transducin β-subunit (Gβ1), which cannot fold without Gγ1 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 Gβ1 production in Gγ1 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.

Full Text

Duke Authors

Cited Authors

  • Lobanova, ES; Finkelstein, S; Skiba, NP; Arshavsky, VY

Published Date

  • June 11, 2013

Published In

Volume / Issue

  • 110 / 24

Start / End Page

  • 9986 - 9991

PubMed ID

  • 23716657

Pubmed Central ID

  • PMC3683722

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1305521110


  • eng

Conference Location

  • United States