Involvement of Oxidative and Endoplasmic Reticulum Stress in <i>RDH12</i>-Related Retinopathies
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 <i>RDH12</i> are primarily associated with autosomal recessive Leber congenital a...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/16/8863 |
| Summary: | 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 <i>RDH12</i> 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 <i>RDH12</i> were created. The WT cells afforded protection from atRAL-induced toxicity and oxidative stress. Mutant <i>RDH12</i> 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 <i>sXBP1</i>, <i>CHOP</i>, and <i>ATF4</i>. Pregabalin, a retinal scavenger, attenuated atRAL-induced ER stress in the mutant <i>RDH12</i> cell lines. A zebrafish <i>rdh12</i> mutant model (<i>rdh12<sup>u533</sup></i> 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 <i>atg12</i> and <i>sod2</i> 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. |
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| ISSN: | 1661-6596 1422-0067 |