Aguilà, M;
Bellingham, J;
Athanasiou, D;
Bevilacqua, D;
Duran, Y;
Maswood, R;
Parfitt, DA;
... Cheetham, ME; + view all
(2020)
AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity.
Human Molecular Genetics
, 29
(8)
pp. 1310-1318.
10.1093/hmg/ddaa049.
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Abstract
Rhodopsin misfolding caused by the P23H mutation is a major cause of autosomal dominant retinitis pigmentosa (adRP), to date there are no effective treatments for adRP. The BiP co-chaperone and reductase ERdj5 (DNAJC10) is part of the ER quality control machinery and previous studies have shown that overexpression of ERdj5 in vitro enhanced the degradation of P23H rhodopsin; whereas knockdown of ERdj5 increased P23H rhodopsin ER retention and aggregation. Here, we investigated the role of ERdj5 in photoreceptor homeostasis in vivo by using an Erdj5 knock-out mouse crossed with the P23H knock-in mouse, and by adeno associated viral (AAV) vector-mediated gene augmentation of ERdj5 in P23H-3 rats. Electroretinogram (ERG) and optical coherence tomography (OCT) of Erdj5−/− and P23H+/−:Erdj5−/− mice showed no effect of ERdj5 ablation on retinal function or photoreceptor survival. Rhodopsin levels and localisation were similar to those of control animals at a range of time points. By contrast, when AAV2/8-ERdj5-HA was subretinally injected into P23H-3 rats, analysis of the full field ERG suggested that overexpression of ERdj5 reduced visual function loss 10 weeks post-injection. This correlated with a significant preservation of photoreceptor cells at 4 and 10 weeks post-injection. Assessment of the outer nuclear layer (ONL) morphology showed preserved ONL thickness and reduced rhodopsin retention in the ONL in the injected superior retina. Overall, these data suggest that manipulation of the ER quality control and ERAD factors to promote mutant protein degradation could be beneficial for the treatment of adRP caused by mutant rhodopsin.
| Type: | Article |
|---|---|
| Title: | AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddaa049 |
| Publisher version: | https://doi.org/10.1093/hmg/ddaa049 |
| Language: | English |
| Additional information: | This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Mutation, homeostasis, electroretinography, genes, mice, knockout, molecular chaperones, oxidoreductase, photoreceptors, quality control, retinitis pigmentosa, rhodopsin, vision, |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10093957 |
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