ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model

Abstract Retinitis Pigmentosa (RP) is a blinding disease that arises from loss of rods and subsequently cones. The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that mirrors RP phenotype in patients carrying the orthologous variant. Previously, we found that the P23H rhodopsi...

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Autores principales:	Eun-Jin Lee, Priscilla Chan, Leon Chea, Kyle Kim, Randal J. Kaufman, Jonathan H. Lin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/53d507943fe448f6ad8a31339d9cc1d5
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spelling	oai:doaj.org-article:53d507943fe448f6ad8a31339d9cc1d52021-12-02T15:08:39ZATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model10.1038/s41598-021-95895-72045-2322https://doaj.org/article/53d507943fe448f6ad8a31339d9cc1d52021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95895-7https://doaj.org/toc/2045-2322Abstract Retinitis Pigmentosa (RP) is a blinding disease that arises from loss of rods and subsequently cones. The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that mirrors RP phenotype in patients carrying the orthologous variant. Previously, we found that the P23H rhodopsin protein was degraded in P23H-KI retinas, and the Unfolded Protein Response (UPR) promoted P23H rhodopsin degradation in heterologous cells in vitro. Here, we investigated the role of a UPR regulator gene, activating transcription factor 6 (Atf6), in rhodopsin protein homeostasis in heterozygous P23H rhodopsin (Rho +/P23H ) mice. Significantly increased rhodopsin protein levels were found in Atf6 −/− Rho +/P23H retinas compared to Atf6 +/− Rho +/P23H retinas at early ages (~ P12), while rhodopsin mRNA levels were not different. The IRE1 pathway of the UPR was hyper-activated in young Atf6 −/− Rho +/P23H retinas, and photoreceptor layer thickness was unchanged at this early age in Rho +/P23H mice lacking Atf6. By contrast, older Atf6 −/− Rho +/P23H mice developed significantly increased retinal degeneration in comparison to Atf6 +/− Rho +/P23H mice in all retinal layers, accompanied by reduced rhodopsin protein levels. Our findings demonstrate that Atf6 is required for efficient clearance of rhodopsin protein in rod photoreceptors expressing P23H rhodopsin, and that loss of Atf6 ultimately accelerates retinal degeneration in P23H-KI mice.Eun-Jin LeePriscilla ChanLeon CheaKyle KimRandal J. KaufmanJonathan H. LinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eun-Jin Lee Priscilla Chan Leon Chea Kyle Kim Randal J. Kaufman Jonathan H. Lin ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model
description	Abstract Retinitis Pigmentosa (RP) is a blinding disease that arises from loss of rods and subsequently cones. The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that mirrors RP phenotype in patients carrying the orthologous variant. Previously, we found that the P23H rhodopsin protein was degraded in P23H-KI retinas, and the Unfolded Protein Response (UPR) promoted P23H rhodopsin degradation in heterologous cells in vitro. Here, we investigated the role of a UPR regulator gene, activating transcription factor 6 (Atf6), in rhodopsin protein homeostasis in heterozygous P23H rhodopsin (Rho +/P23H ) mice. Significantly increased rhodopsin protein levels were found in Atf6 −/− Rho +/P23H retinas compared to Atf6 +/− Rho +/P23H retinas at early ages (~ P12), while rhodopsin mRNA levels were not different. The IRE1 pathway of the UPR was hyper-activated in young Atf6 −/− Rho +/P23H retinas, and photoreceptor layer thickness was unchanged at this early age in Rho +/P23H mice lacking Atf6. By contrast, older Atf6 −/− Rho +/P23H mice developed significantly increased retinal degeneration in comparison to Atf6 +/− Rho +/P23H mice in all retinal layers, accompanied by reduced rhodopsin protein levels. Our findings demonstrate that Atf6 is required for efficient clearance of rhodopsin protein in rod photoreceptors expressing P23H rhodopsin, and that loss of Atf6 ultimately accelerates retinal degeneration in P23H-KI mice.
format	article
author	Eun-Jin Lee Priscilla Chan Leon Chea Kyle Kim Randal J. Kaufman Jonathan H. Lin
author_facet	Eun-Jin Lee Priscilla Chan Leon Chea Kyle Kim Randal J. Kaufman Jonathan H. Lin
author_sort	Eun-Jin Lee
title	ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model
title_short	ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model
title_full	ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model
title_fullStr	ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model
title_full_unstemmed	ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model
title_sort	atf6 is required for efficient rhodopsin clearance and retinal homeostasis in the p23h rho retinitis pigmentosa mouse model
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/53d507943fe448f6ad8a31339d9cc1d5
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ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model

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