AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity

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Fältnamn	Indikatorer	Metadata
000		04206naa a2200457 4500
001		oai:DiVA.org:liu-167311
003		SwePub
008		200702s2020 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-1673112 URI
024	7	a https://doi.org/10.1093/hmg/ddaa0492 DOI
040		a (SwePub)liu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Aguila, Monicau UCL Inst Ophthalmol, England4 aut
245	1 0	a AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity
264		c 2020-03-20
264	1	b OXFORD UNIV PRESS,c 2020
338		a electronic2 rdacarrier
500		a 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
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Neurovetenskaper0 (SwePub)301052 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Neurosciences0 (SwePub)301052 hsv//eng
700	1	a Bellingham, Jamesu UCL Inst Ophthalmol, England4 aut
700	1	a Athanasiou, Dimitrau UCL Inst Ophthalmol, England4 aut
700	1	a Bevilacqua, Dalilau UCL Inst Ophthalmol, England4 aut
700	1	a Duran, Yanaiu UCL Inst Ophthalmol, England4 aut
700	1	a Maswood, Ryeau UCL Inst Ophthalmol, England4 aut
700	1	a Parfitt, David A.u UCL Inst Ophthalmol, England4 aut
700	1	a Iwawaki, Takaou Kanazawa Med Univ, Japan4 aut
700	1	a Spyrou, Ioannisu Linköpings universitet,Avdelningen för klinisk kemi,Medicinska fakulteten4 aut0 (Swepub:liu)ioasp42
700	1	a Smith, Alexander J.u UCL Inst Ophthalmol, England4 aut
700	1	a Ali, Robin R.u UCL Inst Ophthalmol, England4 aut
700	1	a Cheetham, Michael E.u UCL Inst Ophthalmol, England4 aut
710	2	a UCL Inst Ophthalmol, Englandb Kanazawa Med Univ, Japan4 org
773	0	t Human Molecular Geneticsd : OXFORD UNIV PRESSg 29:8, s. 1310-1318q 29:8<1310-1318x 0964-6906x 1460-2083
856	4	u https://liu.diva-portal.org/smash/get/diva2:1450999/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4	u https://academic.oup.com/hmg/article-pdf/29/8/1310/33318690/ddaa049.pdf
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-167311
856	4 8	u https://doi.org/10.1093/hmg/ddaa049

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By the author/editor: Aguila, Monica; Bellingham, Jame ...; Athanasiou, Dimi ...; Bevilacqua, Dali ...; Duran, Yanai; Maswood, Ryea; show more...; Parfitt, David A ...; Iwawaki, Takao; Spyrou, Ioannis; Smith, Alexander ...; Ali, Robin R.; Cheetham, Michae ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

Articles in the publication: Human Molecular ...

By the university: Linköping University

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