Enhanced Endocytosis and Mitochondrial Stress Underlie Severe Retinitis Pigmentosa With RHO P347L Mutant.

Authors

Chenyue Hang, Xinchao Shi, Tianyuan Zhao, Jianqing Li, Ting Zhang, Zhixuan Chen, Yidong Wu, Yuhui Zhou, Shuang Wu, Yutian Jiao, Yazhi Wang, Heng Chen, Junran Sun, Tong Li, Jian Zhang, Huixun Jia, Xiaoling Wan, Xiaosa Li, Jieqiong Chen, Bo Yu, Xiaodong Sun

Published in

Investigative ophthalmology & visual science. Volume 67. Issue 8. Pages 23. Jul 01, 2026.

Abstract

RHO mutations are the primary cause of autosomal dominant retinitis pigmentosa (adRP), with Class 1 mutations typically exhibiting more severe phenotypes than Class 2. This study aims to clarify the mechanistic basis for this clinical disparity by systematically comparing protein degradation pathways, mitochondrial stress, and neuroinflammation.
Humanized mouse lines carrying Class 1 (P347L) or Class 2 (L125R) RHO mutations were generated via CRISPR/Cas9-mediated knock-in. Retinal function, ultrastructure, and transcriptomic profiles were characterized through electroretinography (ERG), transmission electron microscopy (TEM), and RNA-sequencing (RNA-seq). To further elucidate molecular mechanisms, protein trafficking and degradation pathways were analyzed in transfected HEK293T cells using HiBiT extracellular quantification, pharmacological inhibition of lysosomal and proteasomal pathways, and BRET2 visual arrestin recruitment assay.
The P347L mutant failed to undergo efficient outer-segment-directed trafficking and was predominantly degraded via the lysosomal pathway, consistent with its enhanced visual arrestin recruitment and endocytosis. In contrast, the L125R mutant showed protein misfolding and was degraded by both proteasomal and lysosomal pathways. In vivo, P347L mice exhibited more pronounced mitochondrial dysfunction than L125R mice, accompanied by elevated cGMP levels and lysosomal overload. Neuroinflammation was similarly present in both mutants, indicating a shared pathological mechanism rather than a differential contributor.
We propose a pathogenic model in which elevated endocytosis and mitochondrial dysfunction contribute to the accelerated photoreceptor degeneration in RHO P347L-associated adRP.

PMID:
42411866
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.