Autosomal dominant Retinitis Pigmentosa caused by the rhodopsin isoleucine 255 deletion features rapid neuroretinal degeneration, decreased synaptic connectivity, and neuroinflammation

Author:

Cao BowenORCID,Zhu YuORCID,Günter Alexander,Kilger Ellen,Bolz Sylvia,Henes Christine,Mühlfriedel Regine,Seeliger Mathias W.,Paquet-Durand FrançoisORCID,Arango-Gonzalez BlancaORCID,Ueffing MariusORCID

Abstract

AbstractRetinitis Pigmentosa (RP) is a group of inherited retinal diseases that initially affects rod photoreceptors and causes progressive vision loss and blindness. Mutations in rhodopsin (RHO) can cause both autosomal recessive (ar) and dominant (ad) forms of RP, yet, the underlying degenerative mechanisms remain largely unknown, rendering the disease untreatable. Here, we focus on an in-frame, 3-base pair deletion, eliminating the isoleucine residue at codon 255 (i.e., RHOΔI255) and resulting in adRP.We generated a novel knock-in mouse homologous to the humanRHOΔI255mutation. This new mouse model displays a severe disruption of photoreceptor structure and function, as is seen in human patients. Our results indicate that this form of RP is a systems disease of the neuroretina that also impacts neuronal connectivity of bipolar- and horizontal cells, initiates neuroinflammation, and reduces the structural and functional integrity of the retina.Typical for adRP,RhoΔI255mice exhibit primary rod photoreceptor loss, followed by secondary cone degeneration, rhodopsin protein (RHO) mislocalization, progressive shortening of outer segments (OS), and disorganized OS structures. Subsequently, increasing gliosis, morphologic abnormalities of the inner retina, and impaired cone-driven visual function developed. In adRP, a single mutated allele is sufficient to cause the disease, as confirmed here inRhoΔI255/+heterozygous animals, where most photoreceptors were lost within two months after birth. Compared to this, homozygousRhoΔI255/ΔI255mutants exhibit an accelerated onset and even faster progression of retinal degeneration. The degeneration ofRhoΔI255-mutant photoreceptors was linked to the activation of both caspase- and calpain-type proteases, as well as poly(ADP-ribose) polymerase (PARP), indicating a parallel execution of both apoptotic and non-apoptotic processes.In conclusion, our data indicate that this form of RP affects the neuroretina beyond photoreceptor cell loss sharing features typical for other degenerative central nervous systems diseases, an insight, which may bear critical impact to understand and eventually develop treatment for these currently untreatable forms of blindness.Author summaryDominant mutations in the human rhodopsin gene are among the most common causes for the blinding disease retinitis pigmentosa (RP). To date, the underlying pathophysiological mechanisms are still largely unknown and dominant RP remains untreatable. Here, we introduce a new knock-in mouse model carrying the dominant humanRhoΔI255mutation. As in humans, theRhoΔI255mouse suffers from a rapid degeneration of rod photoreceptors followed by subsequent cell death of cone photoreceptors and complete loss of visual function. The new mouse model displays sign of neuroinflammation and the concomitant activation of both apoptotic and non-apoptotic cell death mechanisms. These results will likely stimulate further studies into the degenerative processes governing dominant RP and may facilitate future therapy development for inherited retinal diseases that are still untreatable to this day.

Publisher

Cold Spring Harbor Laboratory

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3