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

ABSTRACT: 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 ?-subunit (G?1) knockout mouse. These rods produce large amounts of transducin ?-subunit (G?1), which cannot fold without G?1 and undergoes intracellular proteolysis instead of forming a transducin ??-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 G?1 production in G?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.

SUBMITTER: Lobanova ES 

PROVIDER: S-EPMC3683722 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature