Noncell-autonomous photoreceptor degeneration in a zebrafish model of choroideremia

Krock, Bryan L.; Bilotta, Joseph; Perkins, Brian D.

doi:10.1073/pnas.0605818104

Cited by 79Retinal Development and DisordersRetinal Diseases and TreatmentsCellular transport and secretion

Noncell-autonomous photoreceptor degeneration in a zebrafish model of choroideremia

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Krock, Bryan L., Bilotta, Joseph, Perkins, Brian D.·2007·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0605818104PMC PMC1810335

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Abstract

Choroideremia is an X-linked hereditary retinal degeneration resulting from mutations in the Rab escort protein-1 (REP1). The Rep1 protein facilitates posttranslational modification of Rab proteins, which regulate intracellular trafficking in the retinal pigment epithelium (RPE) and photoreceptors and are likely involved in the removal of outer segment disk membranes by the RPE. A critical question for potential treatment of choroideremia is whether photoreceptor degeneration results from autonomous defects in opsin transport within the photoreceptor or as a nonautonomous and secondary consequence of RPE degeneration. To address this question, we have characterized the retinal pathology in zebrafish rep1 mutants, which carry a recessive nonsense mutation in the REP1 gene. Zebrafish rep1 mutants exhibit degeneration of the RPE and photoreceptors and complete loss of visual function as measured by electroretinograms. In the mutant RPE, photoreceptor outer segment material was not effectively eliminated, and large vacuoles were observed. However, opsin trafficking in photoreceptors occurred normally. Mosaic analysis revealed that photoreceptor degeneration was nonautonomous and required contact with the mutant RPE as mutant photoreceptors were rescued in wild-type hosts and wild-type photoreceptors degenerated in mutant hosts. We conclude that mutations in REP1 disrupt cellular processes in the RPE, which causes photoreceptor death as a secondary consequence. These results suggest that therapies that correct the RPE may successfully rescue photoreceptor loss in choroideremia.

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Decreased expression of REP1 in the RPE inhibits POS phagosome degradation.
“Decreased expression of REP1 in the RPE has been shown to inhibit POS phagosome degradation (Krock et al., 2007; Gordiyenko et al., 2010).”
From Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis (2015) · cites this paper as Krock et al., 2007

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Authors: Krock, B. L., Bilotta, J., & Perkins, B. D.
Affiliations: Texas A&M University (US)
Western Kentucky University (US)
Corresponding author: Perkins, Brian D.
ORCID: Krock, Bryan L.
Perkins, Brian D.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2007-03-13
Volume: 104
Issue: 11
Pages: 4600-4605
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0605818104
PMC: PMC1810335
OpenAlex: W2032100272
Cited by: 79
References: 41
Citations by year: 2025: 5 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 3 · 2015: 5 · 2014: 3 · 2013: 2 · 2012: 3
FWCI: 2.49
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
OakTrust (Texas A&M University Libraries) (submittedVersion)
Funders: University of Notre Dame
National Institutes of Health
National Center for Research Resources (P20RR016481)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords: choroideremia, REP1, Rab escort protein 1, photoreceptor degeneration, retinal pigment epithelium degeneration, Rab GTPases, mosaic analysis, X-linked retinal degeneration, retinal degeneration treatment
MeSH terms: Alleles, Animals, Disease Models, Animal, Electroretinography, Models, Biological, Mosaicism, Mutation, Pigment Epithelium of Eye, Retinal Degeneration, Time Factors, Zebrafish, Choroideremia, Rod Opsins, Photoreceptor Cells, Vertebrate, Microscopy, Electron, Transmission

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Noncell-autonomous photoreceptor degeneration in a zebrafish model of choroideremia

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