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We acknowledge the assistance of Dr. A. Gimeno and L. Gomez-Segura at the Vivarium facility with antibody generation in rabbits and with animal procedures. We kindly acknowledge the excellent technical assistance of Dr. Benjamin Torrejon with image acquisition at the Leica TCS-SL at the CCiT-UB. We thank Dr. Cristina Munoz for her advice on ER stress analysis. J.A. and P.L. acknowledge financial support from the Spanish Ministry of Economy and Competitiveness through the Severo Ochoa program for Centres of Excellence in R&D (SEV-2015-0522), from Fundacio Privada Cellex, Fundacion Mig-Puig, from Generalitat de Catalunya through the CERCA program, and Laser lab Europe (No. 654148). Pdl.V. was supported by a grant from the Spanish Instituto de Salud Carlos III [ISCIII] (PI18/00754). A.M. acknowledges funding from the Spanish Ministry of Economy and Competitiveness (MINECO): BFU2016-80583-R; from the Ramon Areces Foundation: XVII Edition on Rare Diseases; and from Generalitat de Catalunya through the CERCA program. J.A., P.L., and A.M. acknowledge funding from the Foundation La Marato de TV3: ref. 20141730.

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GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress

Publicated to:Cell Death & Disease. 11 (1): 62- - 2020-01-24 11(1), DOI: 10.1038/s41419-020-2255-0

Authors: Plana-Bonamaisó, A; López-Begines, S; Méndez, A; Andilla, J; Loza-Alvarez, P; Fidalgo, MJ; Estanyol, JM; de la Villa, P

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Abstract

Loss-of-function mutations in the retinal degeneration 3 (RD3) gene cause inherited retinopathy with impaired rod and cone function and fast retinal degeneration in patients and in the natural strain of rd3 mice. The underlying physiopathology mechanisms are not well understood. We previously proposed that guanylate cyclase-activating proteins (GCAPs) might be key Ca2+-sensors mediating the physiopathology of this disorder, based on the demonstrated toxicity of GCAP2 when blocked in its Ca2+-free form at photoreceptor inner segments. We here show that the retinal degeneration in rd3 mice is substantially delayed by GCAPs ablation. While the number of retinal photoreceptor cells is halved in 6 weeks in rd3 mice, it takes 8 months to halve in rd3/rd3 GCAPs(-/-) mice. Although this substantial morphological rescue does not correlate with recovery of visual function due to very diminished guanylate cyclase activity in rd3 mice, it is very informative of the mechanisms underlying photoreceptor cell death. By showing that GCAP2 is mostly in its Ca2+-free-phosphorylated state in rd3 mice, we infer that the [Ca2+](i) at rod inner segments is permanently low. GCAPs are therefore retained at the inner segment in their Ca2+-free, guanylate cyclase activator state. We show that in this conformational state GCAPs induce endoplasmic reticulum (ER) stress, mitochondrial swelling, and cell death. ER stress and mitochondrial swelling are early hallmarks of rd3 retinas preceding photoreceptor cell death, that are substantially rescued by GCAPs ablation. By revealing the involvement of GCAPs-induced ER stress in the physiopathology of Leber's congenital amaurosis 12 (LCA12), this work will aid to guide novel therapies to preserve retinal integrity in LCA12 patients to expand the window for gene therapy intervention to restore vision.

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