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  • Aguila, MonicaUCL Inst Ophthalmol, England (author)

AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • 2020-03-20
  • OXFORD UNIV PRESS,2020
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-167311
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-167311URI
  • https://doi.org/10.1093/hmg/ddaa049DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding Agencies|Wellcome TrustWellcome Trust [092621, 205041, 099173]; Retina UK [GR576]; Fight for Sight; Foundation Fighting Blindness USA; UCL and Moorfields Eye Hospital NIHR Biomedical Research Centre
  • 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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Added entries (persons, corporate bodies, meetings, titles ...)

  • Bellingham, JamesUCL Inst Ophthalmol, England (author)
  • Athanasiou, DimitraUCL Inst Ophthalmol, England (author)
  • Bevilacqua, DalilaUCL Inst Ophthalmol, England (author)
  • Duran, YanaiUCL Inst Ophthalmol, England (author)
  • Maswood, RyeaUCL Inst Ophthalmol, England (author)
  • Parfitt, David A.UCL Inst Ophthalmol, England (author)
  • Iwawaki, TakaoKanazawa Med Univ, Japan (author)
  • Spyrou, IoannisLinköpings universitet,Avdelningen för klinisk kemi,Medicinska fakulteten(Swepub:liu)ioasp42 (author)
  • Smith, Alexander J.UCL Inst Ophthalmol, England (author)
  • Ali, Robin R.UCL Inst Ophthalmol, England (author)
  • Cheetham, Michael E.UCL Inst Ophthalmol, England (author)
  • UCL Inst Ophthalmol, EnglandKanazawa Med Univ, Japan (creator_code:org_t)

Related titles

  • In:Human Molecular Genetics: OXFORD UNIV PRESS29:8, s. 1310-13180964-69061460-2083

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