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Cell death & disease

Unfolded protein response-induced dysregulation of calcium homeostasis promotes retinal degeneration in rat models of autosomal dominant retinitis pigmentosa.


PMID 26844699

Abstract

The molecular mechanism of autosomal dominant retinitis pigmentosa (ADRP) in rats is closely associated with a persistently activated unfolded protein response (UPR). If unchecked, the UPR might trigger apoptosis, leading to photoreceptor death. One of the UPR-activated cellular signaling culminating in apoptotic photoreceptor cell death is linked to an increase in intracellular Ca(2+). Therefore, we validated whether ADRP retinas experience a cytosolic Ca(2+) overload, and whether sustained UPR in the wild-type retina could promote retinal degeneration through Ca(2+)-mediated calpain activation. We performed an ex vivo experiment to measure intracellular Ca(2+) in ADRP retinas as well as to detect the expression levels of proteins that act as Ca(2+) sensors. In separate experiments with the subretinal injection of tunicamycin (UPR inducer) and a mixture of calcium ionophore (A231278) and thapsigargin (SERCA2b inhibitor) we assessed the consequences of a sustained UPR activation and increased intracellular Ca(2+) in the wild-type retina, respectively, by performing scotopic ERG, histological, and western blot analyses. Results of the study revealed that induced UPR in the retina activates calpain-mediated signaling, and increased intracellular Ca(2+) is capable of promoting retinal degeneration. A significant decline in ERG amplitudes at 6 weeks post treatment was associated with photoreceptor cell loss that occurred through calpain-activated CDK5-pJNK-Csp3/7 pathway. Similar calpain activation was found in ADRP rat retinas. A twofold increase in intracellular Ca(2+) and up- and downregulations of ER membrane-associated Ca(2+)-regulated IP3R channels and SERCA2b transporters were detected. Therefore, sustained UPR activation in the ADRP rat retinas could promote retinal degeneration through increased intracellular Ca(2+) and calpain-mediated apoptosis.

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T7765
Tunicamycin from Streptomyces sp.