4.5 Article

Subcellular localization of mutant P23H rhodopsin in an RFP fusion knock-in mouse model of retinitis pigmentosa

期刊

DISEASE MODELS & MECHANISMS
卷 15, 期 5, 页码 -

出版社

COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.049336

关键词

Autosomal dominant; Electron microscopy; Electroretinography; Fluorescence imaging; Retinal degeneration; Rhodopsin

资金

  1. National Institutes of Health [R01-EY01173, R01EY026545, R01 EY031949, P30EY002520, P30CA125123, F32-EY027171]
  2. SunRegen Healthcare AG
  3. Knights Templar Eye Foundation

向作者/读者索取更多资源

The P23H-Rho-RFP mouse model provides a useful tool for studying the pathology and treatment of P23H-Rho and adRP. Mutant rod cells undergo an adaptive process that prolongs survival despite unfolded protein accumulation in the endoplasmic reticulum.
The P23H mutation in rhodopsin (Rho), the rod visual pigment, is the most common allele associated with autosomal-dominant retinitis pigmentosa (adRP). The fate of misfolded mutant Rho in rod photoreceptors has yet to be elucidated. We generated a new mouse model, in which the P23H-Rho mutant allele is fused to the fluorescent protein Tag-RFP-T (P23HhRhoRFP). In heterozygotes, outer segments formed, and wild-type (WT) rhodopsin was properly localized, but mutant P23H-Rho protein was mislocalized in the inner segments. Heterozygotes exhibited slowly progressing retinal degeneration. Mislocalized P23HhRhoRFP was contained in greatly expanded endoplasmic reticulum (ER) membranes. Quantification of mRNA for markers of ER stress and the unfolded protein response revealed little or no increases. mRNA levels for both the mutant human rhodopsin allele and the WT mouse rhodopsin were reduced, but protein levels revealed selective degradation of the mutant protein. These results suggest that the mutant rods undergo an adaptative process that prolongs survival despite unfolded protein accumulation in the ER. The P23H-Rho-RFP mouse may represent a useful tool for the future study of the pathology and treatment of P23H-Rho and adRP. This article has an associated First Person interview with the first author of the paper.

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