Abstract
BackgroundRetinitis 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.MethodsBy 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).ResultsThe 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.ConclusionThis 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.
Highlights
Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease yet with no effective treatment available
Cone PR degeneration is exacerbated due to sigma-1 receptor (S1R) knockout in rd10 mice In order to determine S1R-specific cellular and molecular responses during PR degeneration, we used a crossed line of rd10/S1R−/− to compare with rd10 mice
Cone PR degeneration was compared between rd10/S1R−/− and rd10/S1R +/+ mice via PNA labeling on retinal sections (Fig. 1)
Summary
Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease yet with no effective treatment available. Pharmacological activation of S1R was recently shown to rescue cones in the rd mouse, a rod Pde6b mutant that recapitulates the RP pathology of autonomous rod degeneration followed by secondary death of cones. The sigma-1 receptor (S1R) is a molecular chaperone that modulates a variety of cellular activities. While ubiquitously distributed, it is abundant in the central and peripheral nervous systems [1]. Wang et al [23] just reported that intraperitoneal repeat injections of S1R agonist (+)-pentazocine substantially rescued cones in the rd mouse model (rod Pde6b mutation) of retinitis pigmentosa (RP). The rd model exemplifies RP with autonomous rod degeneration and secondary cone death [25]. It is imperative to understand how S1R influences PR death in rd mice
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