Loss of αA or αB-Crystallin Accelerates Photoreceptor Cell Death in a Mouse Model of P23H Autosomal Dominant Retinitis Pigmentosa.

Tiantian Wang,Patrice E Fort,Lin Jia,Jingyu Yao,David N Zacks

doi:10.3390/ijms23010070

Abstract

Inherited retinal degenerations (IRD) are a leading cause of visual impairment and can result from mutations in any one of a multitude of genes. Mutations in the light-sensing protein rhodopsin (RHO) is a leading cause of IRD with the most common of those being a missense mutation that results in substitution of proline-23 with histidine. This variant, also known as P23H-RHO, results in rhodopsin misfolding, initiation of endoplasmic reticulum stress, the unfolded protein response, and activation of cell death pathways. In this study, we investigate the effect of α-crystallins on photoreceptor survival in a mouse model of IRD secondary to P23H-RHO. We find that knockout of either αA- or αB-crystallin results in increased intraretinal inflammation, activation of apoptosis and necroptosis, and photoreceptor death. Our data suggest an important role for the ⍺-crystallins in regulating photoreceptor survival in the P23H-RHO mouse model of IRD.

Highlights

Contrary to our expectation, α-crystallin deficiency did not alter produce RhoP23H/+ (P23H)-RHO protein folding or autophagy activation in the photoreceptors of P23H-RHO mice. These results suggest that α-crystallin exerts its protective roles on photoreceptor survival in the P23H-RHO by regulating the activation of inflammation and cell death pathways
Though typically studied for their structural role in the ocular lens and maintenance of its transparency, it has become increasingly recognized that crystallin proteins play important other functions, including in the retina
Α-crystallins belong to the small heat shock proteins and have gained attention for their neuroprotective properties [23,50,51] Over the last decade, several groups have demonstrated that lack of one or both α-crystallin proteins was associated with increased neurodegeneration in diabetic retinopathy, endophthalmitis, uveitis, or retinal tear [52,53]

Summary

Introduction

Inherited retinal degeneration (IRD) is a significant cause of progressive, irreversible blindness throughout the world. Mutations in over 300 genes have been identified as causing IRD [1,2], and transmission in autosomal dominant, autosomal recessive, and x-linked patterns have been described [3,4,5]. Autosomal dominant retinitis pigmentosa (adRP) derives from inherited mutations in a variety of retinal genes, and, similar to other

Methods

Results

Conclusion