Effect of protein homeostasis modulation in primary cone degeneration

Abstract

AbstractPurposeDegenerative cone disorders are an important group of inherited retinal degenerations as they severely disable visual acuity and color vision, causing a major impact on the quality of life of affected patients. These disorders are commonly classified as cone dystrophies and achromatopsia. The cone photoreceptor function loss‐1 (cpfl1) mutant mouse is a model for primary cone degeneration and shares a similar phenotype to patients with complete achromatopsia. Cpfl1 mutation affects the cone‐specific PDE6 gene, leading to a cGMP accumulation, increased Ca+ influx, and cell death. Moreover, M‐, S‐opsin and cone‐specific transducin mislocalization to the cell body have been reported (Trifunovic et al., 2016). Previously, the inhibition of valosin‐containing protein (VCP, an ATPase involved in the (ERAD)) has proven to be protective in different models of autosomal dominant retinitis pigmentosa restoring protein trafficking (Arango‐Gonzalez et al., 2020; Sen et al., 2021). This study aims to assess whether VCP inhibition can also be protective against cone photoreceptor cell death in a cpfl1 retinal organotypic culture system.MethodsCpfl1 retinal explants were maintained in serum‐free conditions and treated with two VCP inhibitors, ML240 and NMS‐873, from PN14 until PN24 (peak of cone degeneration). Photoreceptor cell survival, cone morphology, and opsin expression were evaluated by TUNEL staining, cell row quantification, and immunostaining.ResultsVCP inhibition resulted in an increased number of cell rows in the ONL of the treated explants compared with the control groups. The treated retinas also showed an improved cone morphology and a significant restoration of cone density up to levels similar to those observed in the wild type.ConclusionsOur results suggest that modulation of protein homeostasis through VCP inhibition is protective in primary cone degeneration.