Cone degeneration is triggered by the absence of USH1 proteins but prevented by antioxidant treatments

Alix Trouillet,Ivana Ivkovic,David Godefroy,Diego García-Ayuso,Aziz El-Amraoui,Manuel Simonutti,José A Sahel,Julie Dégardin,Christine Petit,Elisabeth Dubus,Amrit Estivalet,Serge Picaud,Iman Sahly

doi:10.1038/s41598-018-20171-0

Abstract

Usher syndrome type 1 (USH1) is a major cause of inherited deafness and blindness in humans. The eye disorder is often referred to as retinitis pigmentosa, which is characterized by a secondary cone degeneration following the rod loss. The development of treatments to prevent retinal degeneration has been hampered by the lack of clear evidence for retinal degeneration in mutant mice deficient for the Ush1 genes, which instead faithfully mimic the hearing deficit. We show that, under normal housing conditions, Ush1g−/− and Ush1c−/− albino mice have dysfunctional cone photoreceptors whereas pigmented knockout animals have normal photoreceptors. The key involvement of oxidative stress in photoreceptor apoptosis and the ensued retinal gliosis were further confirmed by their prevention when the mutant mice are reared under darkness and/or supplemented with antioxidants. The primary degeneration of cone photoreceptors contrasts with the typical forms of retinitis pigmentosa. Altogether, we propose that oxidative stress probably accounts for the high clinical heterogeneity among USH1 siblings, which also unveils potential targets for blindness prevention.

Highlights

Usher syndrome type 1 (USH1) is the most severe form of inherited deafness and blindness in humans[1,2,3] with a prevalence recently estimated from 1/6000 to 1/10000
In vivo optical coherence tomography (OCT) (Fig. 1e,f) and histological immunostaining (Fig. 1g–i) showed the retina to have a normal thickness and architecture, with a normal photoreceptor organization. This absence of morphological or functional abnormalities in Ush1g−/− and Ush1c−/− C57Bl/6 J mice was consistent with the lack of retinal degeneration observed in previously reported harmonin mouse models[15,16,17]
We investigated whether the retinal phenotype uncovered in the albino BALB/cJ background resulted from greater exposure to light, by keeping the Ush1g−/− albino mice in total darkness between the ages of two and six months, as this phenotype was already evident at three months in mice exposed to light (Fig. 2)

Summary

Introduction

Usher syndrome type 1 (USH1) is the most severe form of inherited deafness and blindness in humans[1,2,3] with a prevalence recently estimated from 1/6000 to 1/10000. Studies have housed mice in different light conditions to determine if photoreceptors were more susceptible to high photooxidative stress in Ush[1] mouse models These studies produced conflicting findings with myosinVIIa-defective shaker[1] mice being either more resistant to acute light damage than controls[32], or showing rod degeneration upon exposure to moderate light (1500 lux) for 6 months or to constant light for 6 days[33]. To study these issues, we developed two murine models of USH1 mice, defective for either Ush1c or Ush1g genes[34,35], which encode the two scaffolding proteins, harmonin and Sans, respectively. In these two new models, we found greater changes occurring in cone photoreceptors under a set of specific conditions

Methods

Results

Conclusion