12/30/2023 0 Comments Jstock bollinger indicatorsIn particular, whether S1R influences this process is not known. While apoptosis has been well-documented, necroptosis of cones is a relatively new mechanism not well understood in rd10 retinas. It is therefore imperative to understand how S1R influences PR death in rd10 mice.Ī recent report distinguishes that apoptosis and necroptosis (programed necrosis) are chief mechanisms responsible for the sequential death of rods and cones, respectively. ![]() As it is not yet practical to correct RP mutations individually, investigation of a common pathway, e.g., S1R, a target suitable for pharmacological interventions, is highly significant. The rd10 model exemplifies RP with autonomous rod degeneration and secondary cone death. RP is a heterogeneous group of inherited retinal degenerations linked to thousands of mutations in over 70 human genes. just reported that intraperitoneal repeat injections of S1R agonist (+)-pentazocine substantially rescued cones in the rd10 mouse model (rod Pde6b mutation) of retinitis pigmentosa (RP). An important recent development is that S1R was found to protect RGCs (for review, see ), in RGC-damage mouse models either treated with S1R agonists or compared between wild type and S1R knockout (S1R −/−). The recently solved S1R crystal structure is expected to accelerate therapeutic development of S1R drugs.ĭegeneration of retinal neurons, mainly photoreceptors (PRs, i.e., rods and cones) and retinal ganglion cells (RGCs), shares considerable patho-mechanisms with neurodegenerative brain diseases. Thus, S1R appears to be a potential anti-neurodegenerative therapeutic target. ![]() ![]() Abnormal S1R subcellular localization was found in postmortem brain samples of neurodegenerative diseases. Furthermore, human S1R mutations were linked to ALS and frontotemporal lobar degeneration. A protective role of S1R has been increasingly reported in neurodegenerative disease models, including Parkinson’s, Alzheimer’s, Huntington’s and ALS. Many S1R-binding compounds have been identified some are in clinical use (e.g., as antidepressants) or trials. The S1R binding site is the target of numerous pharmacological studies on psychotic disorders, locomotor activity, threat response, and pain etc. While ubiquitously distributed, it is abundant in the central and peripheral nervous systems. The sigma-1 receptor (S1R) is a molecular chaperone that modulates a variety of cellular activities. 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. 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. 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. Methodsīy 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). The mechanisms underlying the S1R protection for cones are not understood in detail. 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 sigma-1 receptor (S1R), a ligand-regulated chaperone, emerges as a potential retina-protective therapeutic target. ![]() Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease yet with no effective treatment available.
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