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

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.

Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation

“…We observed an increase in methylation of SNTG1 at 9 months, which could lead to decreased expression of the protein. We also observed decreased methylation of the USH1G, a gene critical to proper visual and auditory function [50]. Moreover, we observed increased methylation of the PCCA, which is an enzyme critical to proper function of the tricarboxylic acid (aka Krebs or TCA) cycle and energy production in muscle, both cardiac and skeletal [51,52].…”

Bone Marrow-Derived Mononuclear Cell Transplants Decrease Retinal Gliosis in Two Animal Models of Inherited Photoreceptor Degeneration

“…Since both in RP and AMD there are many genetic defects involved, gene therapy may not be as useful as it has been in other retinal diseases with few known genetic defects, such as Leber congenital amaurosis [ 10 ]. Thus, the research efforts have been directed to develop pharmacological or cellular therapies that could slow photoreceptor loss and/or replace the lost photoreceptors [ 9 , 10 , 28 , 29 , 30 , 31 , 32 ]. Stem cells (SC) can theoretically perform both these actions [ 33 , 34 ].…”

Novel Usher syndrome pathogenic variants identified in cases with hearing and vision loss

“…Novel therapies that target USH2A show great promise as retinal degeneration in USH2A patients can be rescued using antisense oligonucleotide-based therapy targeting cryptic splicing variants [7]. Additionally, antioxidant-based therapies have also shown great promise in preventing cone degeneration in USH1 mice, which is linked to oxidative stress [8]. Oxidative stress has well-established roles in many retinal dystrophies, where polymorphisms in GLO1 may explain RP susceptibility and clinical heterogeneity [9].…”