PUBLICATION
Involvement of Oxidative and Endoplasmic Reticulum Stress in RDH12-Related Retinopathies
- Authors
- Sarkar, H., Toms, M., Moosajee, M.
- ID
- ZDB-PUB-210828-37
- Date
- 2021
- Source
- International Journal of Molecular Sciences 22(16): (Journal)
- Registered Authors
- Keywords
- all-trans retinal, autophagy, endoplasmic reticulum stress, oxidative stress, pregabalin, retinol dehydrogenase 12, zebrafish
- MeSH Terms
-
- Alcohol Oxidoreductases/antagonists & inhibitors
- Alcohol Oxidoreductases/genetics
- Alcohol Oxidoreductases/metabolism*
- Animals
- Apoptosis*
- Autophagy
- CRISPR-Cas Systems
- Endoplasmic Reticulum Stress*
- HEK293 Cells
- Humans
- Mutation*
- Oxidative Stress*
- Retinal Diseases/etiology
- Retinal Diseases/metabolism
- Retinal Diseases/pathology*
- Zebrafish
- PubMed
- 34445569 Full text @ Int. J. Mol. Sci.
Citation
Sarkar, H., Toms, M., Moosajee, M. (2021) Involvement of Oxidative and Endoplasmic Reticulum Stress in RDH12-Related Retinopathies. International Journal of Molecular Sciences. 22(16):.
Abstract
Retinol dehydrogenase 12 (RDH12) is expressed in photoreceptor inner segments and catalyses the reduction of all-trans retinal (atRAL) to all-trans retinol (atROL), as part of the visual cycle. Mutations in RDH12 are primarily associated with autosomal recessive Leber congenital amaurosis. To further our understanding of the disease mechanisms, HEK-293 cell lines expressing wildtype (WT) and mutant RDH12 were created. The WT cells afforded protection from atRAL-induced toxicity and oxidative stress. Mutant RDH12 cells displayed reduced protein expression and activity, with an inability to protect cells from atRAL toxicity, inducing oxidative and endoplasmic reticulum (ER) stress, with upregulation of sXBP1, CHOP, and ATF4. Pregabalin, a retinal scavenger, attenuated atRAL-induced ER stress in the mutant RDH12 cell lines. A zebrafish rdh12 mutant model (rdh12u533 c.17_23del; p.(Val6AlafsTer5)) was generated through CRISPR-Cas9 gene editing. Mutant fish showed disrupted phagocytosis through transmission electron microscopy, with increased phagosome size at 12 months post-fertilisation. Rhodopsin mislocalisation and reduced expression of atg12 and sod2 indicated early signs of a rod-predominant degeneration. A lack of functional RDH12 results in ER and oxidative stress representing key pathways to be targeted for potential therapeutics.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping