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• W4384697917 abstract "ABSTRACT Inherited retinal degeneration (IRD) refers to a group of untreatable blinding diseases characterized by a progressive loss of photoreceptors. IRD pathology is often linked to an excessive activation of cyclic nucleotide-gated channels (CNGC) leading to Na + – and Ca 2+ -influx, subsequent activation of voltage-gated Ca 2+ -channels (VGCC), and further Ca 2+ influx. However, whether and how exactly intracellular Ca 2+ overload contributes to photoreceptor degeneration is still controversial. Here, we used whole-retina and single-cell RNA-sequencing to compare gene expression between the rd1 mouse model for IRD and wild-type ( wt ) mice. Differentially expressed genes were linked to several Ca 2+ –signalling related pathways. To explore this further, organotypic retinal explant cultures derived from rd1 and wt mice were treated with the intracellular Ca 2+ -chelator BAPTA-AM and with inhibitors for different Ca 2+ -permeable channels, including CNGC, L-type VGCC, T-type VGCC, Ca 2+ -release-activated channel (CRAC), and Na + /Ca 2+ exchanger (NCX). Moreover, we employed the compound NA-184 to selectively inhibit the Ca 2+ -dependent protease calpain-2. The overall activity of poly(ADP-ribose) polymerases (PARPs), sirtuin-type histone-deacetylases, calpains, as well as the activation of calpain-1, and –2 were analysed in situ on retinal tissue sections. Cell viability was assessed via the TUNEL assay. While rd1 photoreceptor cell death was reduced by BAPTA-AM, the effects of Ca 2+ -channel blockers were ambiguous, with T-type VGCC and NCX inhibition showing protection, while blocking CNGC and CRAC was detrimental. Activity of calpains and PARPs generally followed similar trends as cell death. Remarkably, sirtuin activity and calpain-1 activation was associated with photoreceptor protection, while calpain-2 activity was linked to degeneration. Accordingly, the calpain-2 inhibitor NA-184 protected rd1 photoreceptors. Together, these results indicate that Ca 2+ overload in rd1 photoreceptors may be triggered by T-type VGCC in conjunction with NCX. High Ca 2+ -levels likely suppress the protective activity of calpain-1 and promote neurodegeneration via activation of calpain-2. Our study details the complexity of Ca 2+ -signalling in photoreceptors and emphasizes the importance of identifying and targeting degenerative processes to achieve a therapeutic benefit for IRD." @default.
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• W4384697917 date "2023-07-18" @default.
• W4384697917 modified "2023-10-16" @default.
• W4384697917 title "Inherited retinal degeneration: T-type voltage-gated channels, Na⁺/Ca²⁺-exchanger and calpain-2 promote photoreceptor cell death" @default.
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• W4384697917 doi "https://doi.org/10.1101/2023.07.16.549200" @default.
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