| 1. |
- 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. |
- Shackelford, Nancy, et al.
(författare)
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Isolation predicts compositional change after discrete disturbances in a global meta-study
- 2017
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Ingår i: Ecography. - : John Wiley & Sons. - 0906-7590 .- 1600-0587. ; 40:11, s. 1256-1266
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Tidskriftsartikel (refereegranskat)abstract
- Globally, anthropogenic disturbances are occurring at unprecedented rates and over extensive spatial and temporal scales. Human activities also affect natural disturbances, prompting shifts in their timing and intensities. Thus, there is an urgent need to understand and predict the response of ecosystems to disturbance. In this study, we investigated whether there are general determinants of community response to disturbance across different community types, locations, and disturbance events. We compiled 14 case studies of community response to disturbance from four continents, twelve aquatic and terrestrial ecosystem types, and eight different types of disturbance. We used community compositional differences and species richness to indicate community response. We used mixed-effects modeling to test the relationship between each of these response metrics and four potential explanatory factors: regional species pool size, isolation, number of generations passed, and relative disturbance intensity. We found that compositional similarity was higher between pre- and post-disturbance communities when the disturbed community was connected to adjacent undisturbed habitat. The number of generations that had passed since the disturbance event was a significant, but weak, predictor of community compositional change; two communities were responsible for the observed relationship. We found no significant relationships between the factors we tested and changes in species richness. To our knowledge, this is the first attempt to search for general drivers of community resilience from a diverse set of case studies. The strength of the relationship between compositional change and isolation suggests that it may be informative in resilience research and biodiversity management.
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