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- Aguila, Monica, et al.
(författare)
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AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity
- 2020
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Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 29:8, s. 1310-1318
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Tidskriftsartikel (refereegranskat)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 endoplasmic reticulum (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 knockout 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 of Erdj5(-/-) and P23H(+/-):Erdj5(-/-) mice showed no effect of ERdj5 ablation on retinal function or photoreceptor survival. Rhodopsin levels and localization 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 (PI). This correlated with a significant preservation of photoreceptor cells at 4 and 10 weeks PI. 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 ER-associated degradation factors to promote mutant protein degradation could be beneficial for the treatment of adRP caused by mutant rhodopsin.
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| 2. |
- Farjon, Aljos, et al.
(författare)
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Early Pleistocene conifer macrofossils from Happisburgh, Norfolk, UK, and their environmental implications for early hominin occupation
- 2020
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Ingår i: Quaternary Science Reviews. - : Elsevier. - 0277-3791 .- 1873-457X. ; 232
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Tidskriftsartikel (refereegranskat)abstract
- Continuing coastal erosion in the vicinity of Happisburgh in north Norfolk has revealed archaeological sites documenting early human presence during at least two episodes in the Early and early Middle Pleistocene. At Happisburgh 3, the oldest archaeological site in northern Europe (approximately 900,000 years old) finds include at least 80 flint artefacts and human footprints associated with abundant, well-preserved organic remains. The deposits consist of gravels and estuarine sands and silts contained within a complex of channels, which accumulated in the estuary of a large river, probably the ancestral River Thames. The environmental remains reflect a slow-flowing tidal river, at the limit of tidal influence, and a grassland valley bordered by conifer-dominated woodland. Analyses of the pollen, wood, cones and leaves have identified a diversity of coniferous taxa, with some unexpected central and southern European elements (Pinus mugo ssp. mugo, Pinus mugo ssp. rotundata and Juniperus thurifera) indicating a type of coniferous woodland no longer present in Europe today. Here we present the conifer finds and their environmental implications. A new multi-proxy consensus palaeoclimate reconstruction, using conifer and beetle mutual climatic ranges, confirms and refines previous indications of a more continental climate than today, with significantly colder winters. These results provide a new perspective for understanding the climate and environment encountered by Early Pleistocene hominins at the northernmost limit of their range.
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