scholarly journals AAV Delivery of Wild-Type Rhodopsin Preserves Retinal Function in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

2011 ◽  
Vol 22 (5) ◽  
pp. 567-575 ◽  
Author(s):  
Haoyu Mao ◽  
Thomas James ◽  
Alison Schwein ◽  
Arseniy E. Shabashvili ◽  
William W. Hauswirth ◽  
...  
Keyword(s):  
Mouse Model ◽  
Retinitis Pigmentosa ◽  
Autosomal Dominant ◽  
Retinal Function ◽  
Wild Type ◽  
Autosomal Dominant Retinitis Pigmentosa

scholarly journals The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation

2002 ◽  
Vol 115 (14) ◽  
pp. 2907-2918 ◽  
Author(s):  
Richard S. Saliba ◽  
Peter M. G. Munro ◽  
Philip J. Luthert ◽  
Michael E. Cheetham
Keyword(s):  
Quality Control ◽  
Retinitis Pigmentosa ◽  
Autosomal Dominant ◽  
Cultured Cells ◽  
State Level ◽  
Detailed Examination ◽  
Mutant Protein ◽  
Wild Type ◽  
Autosomal Dominant Retinitis Pigmentosa ◽  
Aggresome Formation

Mutations in the photopigment rhodopsin are the major cause of autosomal dominant retinitis pigmentosa. The majority of mutations in rhodopsin lead to misfolding of the protein. Through the detailed examination of P23H and K296E mutant opsin processing in COS-7 cells, we have shown that the mutant protein does not accumulate in the Golgi, as previously thought, instead it forms aggregates that have many of the characteristic features of an aggresome. The aggregates form close to the centrosome and lead to the dispersal of the Golgi apparatus. Furthermore, these aggregates are ubiquitinated, recruit cellular chaperones and disrupt the intermediate filament network. Mutant opsin expression can disrupt the processing of normal opsin, as co-transfection revealed that the wild-type protein is recruited to mutant opsin aggregates. The degradation of mutant opsin is dependent on the proteasome machinery. Unlike the situation with ΔF508-CFTR, proteasome inhibition does not lead to a marked increase in aggresome formation but increases the retention of the protein within the ER, suggesting that the proteasome is required for the efficient retrotranslocation of the mutant protein. Inhibition of N-linked glycosylation with tunicamycin leads to the selective retention of the mutant protein within the ER and increases the steady state level of mutant opsin. Glycosylation, however, has no influence on the biogenesis and targeting of wild-type opsin in cultured cells. This demonstrates that N-linked glycosylation is required for ER-associated degradation of the mutant protein but is not essential for the quality control of opsin folding. The addition of 9-cis-retinal to the media increased the amount of P23H, but not K296E, that was soluble and reached the plasma membrane. These data show that rhodopsin autosomal dominant retinitis pigmentosa is similar to many other neurodegenerative diseases in which the formation of intracellular protein aggregates is central to disease pathogenesis, and they suggest a mechanism for disease dominance.

scholarly journals Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

PLoS ONE ◽  
2016 ◽  
Vol 11 (5) ◽  
pp. e0154779 ◽  
Author(s):  
Yogesh Bhootada ◽  
Pravallika Kotla ◽  
Sergei Zolotukhin ◽  
Oleg Gorbatyuk ◽  
Zsuzsanna Bebok ◽  
...  
Keyword(s):  
Mouse Model ◽  
Retinitis Pigmentosa ◽  
Er Stress ◽  
Autosomal Dominant ◽  
Autosomal Dominant Retinitis Pigmentosa
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