Background
Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease yet with no effective treatment available. The sigma-1 receptor (S1R), a ligand-regulated chaperone, emerges as a potential retina-protective therapeutic target. In particular, pharmacological activation of S1R was recently shown to rescue cones in the rd10 mouse, a rod Pde6b mutant that recapitulates the RP pathology of autonomous rod degeneration followed by secondary death of cones. The mechanisms underlying the S1R protection for cones are not understood in detail.
Conclusion
This study reveals previously uncharacterized S1R-associated mechanisms during rd10 photoreceptor degeneration, including S1R's influences on necroptosis and autophagy as well as its biphasic role in rod degeneration upstream of cone death.
Methods
By rearing rd10/S1R-/- and rd10/S1R+/+ mice in dim light to decelerate rapid rod/cone degeneration, we were able to compare their retinal biochemistry, histology and functions throughout postnatal 3-6 weeks (3 W-6 W).
Results
The receptor-interacting protein kinases (RIP1/RIP3) and their interaction (proximity ligation) dramatically up-regulated after 5 W in rd10/S1R-/- (versus rd10/S1R+/+) retinas, indicative of intensified necroptosis activation, which was accompanied by exacerbated loss of cones. Greater rod loss in rd10/S1R-/- versus rd10/S1R+/+ retinas was evidenced by more cleaved Caspase3 (4 W) and lower rod electro-retinographic a-waves (4 W-6 W), concomitant with reduced LC3-II and CHOP (4 W-6 W), markers of autophagy and endoplasmic reticulum stress response, respectively. However, the opposite occurred at 3 W.