June 2013
Volume 54, Issue 15
ARVO Annual Meeting Abstract  |   June 2013
Insufficient proteasomal activity is a common stress factor in multiple forms of inherited retinal degeneration
Author Affiliations & Notes
  • Ekaterina Lobanova
    Albert Eye Research Institute, Durham, NC
  • Stella Finkelstein
    Albert Eye Research Institute, Durham, NC
  • Nikolai Skiba
    Albert Eye Research Institute, Durham, NC
  • Vadim Arshavsky
    Albert Eye Research Institute, Durham, NC
  • Footnotes
    Commercial Relationships Ekaterina Lobanova, None; Stella Finkelstein, None; Nikolai Skiba, None; Vadim Arshavsky, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 4181. doi:
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      Ekaterina Lobanova, Stella Finkelstein, Nikolai Skiba, Vadim Arshavsky; Insufficient proteasomal activity is a common stress factor in multiple forms of inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4181.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Inherited retinal degenerations affect approximately two million people worldwide. Many of the underlying mutations cause protein misfolding or mistargeting in affected photoreceptors, which imposes significant burden on the protein folding and degradation machinery and may trigger cell death. While studies of other neurodegenerative diseases revealed a strong association between pathology and impaired proteasomal function, this potential stress factor largely escaped the attention of researchers studying degenerative diseases of the retina. Therefore, we explored the status of proteasomal function in several mouse models of retinal degeneration.

Methods: To assess the status of ubiquitin-dependent proteasomal activity in vivo, mice representing various models of retinal degenerations were bred with mice expressing UbG76V-GFP reporter. The lifetime of this reporter in healthy cells is short, whereas its intracellular accumulation is indicative of proteasomal impairment. Reporter accumulation was monitored using immunocytochemistry and Western blotting. Proteolytic activities of proteasomes in retinal lysates were measured using various fluorogenic peptide substrates. Expression levels of proteasome subunits were assessed by Western blotting.

Results: Prominent UbG76V-GFP fluorescence was observed in four mouse models whose photoreceptors are predicted to degrade abnormal amounts of misfolded or mistargeted proteins: 1) Rds mice lacking outer segments and, therefore, required to continuously degrade proteins normally residing in the outer segment. 2) Rhodopsin knockout mice forming only rudimentary outer segments, which also necessitate degradation of outer segment-specific proteins. 3) P23H mice expressing a misfolded rhodopsin mutant. 4) Transducin γ-subunit knockout mice whose rods produce transducin β-subunit unable to fold without the γ-subunit and proteolyzed instead of forming normal transducin trimer. In contrast, no reliable increase in UbG76V-GFP fluorescence was detected in RPE65 knockout rods, which degeneration is thought to be caused by an alternative mechanism: persistent phototransduction activation.

Conclusions: These results establish the prominence of proteasomal impairment across multiple degenerative diseases of the retina, thereby positioning proteasomes as a new promising therapeutic target for treating these debilitating conditions.

Keywords: 695 retinal degenerations: cell biology • 648 photoreceptors • 696 retinal degenerations: hereditary  

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