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Nat. Commun., 2024 Feb 16;15(1):1451 | https://doi.org/10.1038/s41467-024-45748-4
Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa
Sreelakshmi Vasudevan 1, Subhadip Senapati 1,2, Maryanne Pendergast 1 & Paul S.–H. Park 1,*
1Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
2Present address: Prayoga Institute of Education Research, Bengaluru, KA 560116, India.
*Corresponding author: correspondence to Paul S.–H. Park
Abstract
Mutations in rhodopsin can cause it to misfold and lead to retinal degeneration. A distinguishing feature of these mutants in vitro is that they mislocalize and aggregate. It is unclear whether or not these features contribute to retinal degeneration observed in vivo. The effect of P23H and G188R misfolding mutations were examined in a heterologous expression system and knockin mouse models, including a mouse model generated here expressing the G188R rhodopsin mutant. In vitro characterizations demonstrate that both mutants aggregate, with the G188R mutant exhibiting a more severe aggregation profile compared to the P23H mutant. The potential for rhodopsin mutants to aggregate in vivo was assessed by PROTEOSTAT, a dye that labels aggregated proteins. Both mutants mislocalize in photoreceptor cells and PROTEOSTAT staining was detected surrounding the nuclei of photoreceptor cells. The G188R mutant promotes a more severe retinal degeneration phenotype and greater PROTEOSTAT staining compared to that promoted by the P23H mutant. Here, we show that the level of PROTEOSTAT positive cells mirrors the progression and level of photoreceptor cell death, which suggests a potential role for rhodopsin aggregation in retinal degeneration.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-02-20)
- 국외 연구진
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