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A. Griciuc, L. Aron, M. J. Roux, A. Giangrande, M. Ueffing; Cellular Pathways Modulating RhodopsinP23H-Induced Pathology. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2301.
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Understanding the connection between disease-induced neuronal abnormalities and cellular systems controlling neuronal maintenance and function is a prerequisite for successful drug development to target neurodegenerative disorders. Abnormal folding and trafficking of human Rhodopsin is responsible for autosomal dominant Retinitis pigmentosa (RP), an inherited retinal degenerative disorder characterized by loss of photoreceptors. The most frequent Rhodopsin mutation, RhP23H, leads to protein retention in the endoplasmic reticulum (ER), subsequent ER stress and cell death via apoptosis. We aim at characterizing cellular pathways and molecular interactions that modulate RhodopsinP23H-induced cell death.
We made use of cellular models of RP, whereby mutant and wild-type Rhodopsin were overexpressed in several cell types; in addition, we used the recently established drosophila model of RP, in which overexpression of Rh1P37H (the fly equivalent of human RhP23H) driven by the fly Rh1 promoter leads to dominant retinal degeneration. We modified the survival input to photoreceptors by ectopically expressing activated receptor tyrosine kinases (RTKs) or by overexpressing active versions of PI3K/MAPK components and we genetically inhibited the ER-associated degradation (ERAD) machinery. We analyzed the impact of these modifications on Rhodopsin aggregation in vitro and on visual transduction, subcellular trafficking and neuronal survival in drosophila
We observed in vitro that mutant, but not wild-type Rhodopsin accumulates in the ER and interacts with components of the ERAD machinery. Our results suggest that RTK activation or ERAD inhibition can partially rescue the loss of visual activity and the photoreceptor degeneration in the fly.
Selective activation of RTK signaling and/or inhibition of ERAD can partially rescue photoreceptor degeneration in the fly. Further studies are needed to investigate the relevance of these findings with respect to therapeutic intervention in human RP.
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