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 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. neurodegenerative diseases | protein degradation

Decreased Proteasomal Activity Causes Photoreceptor Degeneration in Mice

“…In line with the current study, it was previously shown that proteasome inhibition led to neuronal cell death through caspase-independent pathways. 36 Alternatively, Lobanova et al 37 recently described that insufficient capacity of proteasomes to process abnormally large amounts of misfolded protein causes photoreceptor cell death. The previous and current data may indicate that imbalance between proteasomal activity and amount of its substrate protein causes retinal degeneration.…”

Ubiquitin-independent protein degradation in proteasomes

“…Авторы считают, что причина дегенерации фоторецепторов в этом случае заключается в том, что протеасомы перегружены слишком большим количеством неправильно свёрнутых белков. Они подчеркивают роль протеасомной недостаточности в развитии множественных дегенеративных заболеваний сетчатки [179].…”

Rhodopsin Trafficking and Mistrafficking

“…91 Consistent with this idea, overwhelming the degradation mechanism leads to aberrant homeostasis of proteins and subsequent photoreceptor degeneration. 92 In KIF3A-deficient rods, rhodopsin mislocalization contributes to the degeneration of rod photoreceptors. KIF3A facilitates the transport of rhodopsin along the ciliary plasma membrane of immortalized human retinal pigment epithelial cells (hTert-RPE1), consistent with the proposed role of KIF3A in the trafficking of rhodopsin through the connecting cilia of photoreceptors.…”