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Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration

Arango-Gonzalez, Blanca and Sen, Merve and Guarascio, Rosellina and Ziaka, Kalliopi and del Amo, Eva M. and Hau, Kwan and Poultney, Hannah and Asfahani, Rowan and Urtti, Arto and Chou, Tsui-Fen and Bolz, Sylvia and Deshaies, Raymond J. and Haq, Wadood and Cheetham, Michael E. and Ueffing, Marius (2020) Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20201123-120919400

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Abstract

Due to continuously high production rates of rhodopsin (RHO) and high metabolic activity, photoreceptor neurons are especially vulnerable to defects in proteostasis. A proline to histidine substitution at position 23 (P23H) leads to production of structurally misfolded RHO, causing the most common form of autosomal dominant Retinitis Pigmentosa (adRP) in North America. The AAA-ATPase valosin-containing protein (VCP) extracts misfolded proteins from the ER membrane for cytosolic degradation. Here, we provide the first evidence that inhibition of VCP activity rescues degenerating P23H rod cells and improves their functional properties in P23H transgenic rat and P23H knock-in mouse retinae, both in vitro and in vivo. This improvement correlates with the restoration of the physiological RHO localization to rod outer segments (OS) and properly-assembled OS disks. As a single intravitreal injection suffices to deliver a long-lasting benefit in vivo, we suggest VCP inhibition as a potential therapeutic strategy for adRP patients carrying mutations in the RHO gene.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.11.17.384669DOIDiscussion Paper
ORCID:
AuthorORCID
Arango-Gonzalez, Blanca0000-0002-9045-182X
del Amo, Eva M.0000-0002-5705-4515
Urtti, Arto0000-0001-6064-3102
Chou, Tsui-Fen0000-0003-2410-2186
Deshaies, Raymond J.0000-0002-3671-9354
Cheetham, Michael E.0000-0001-6429-654X
Ueffing, Marius0000-0003-2209-2113
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. This version posted November 19, 2020. This study was supported by funds (to M.Ue. and B.A-G) from FFB (Grant PPA-0717-0719-RAD), Kerstan Foundation, European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie (Grant agreement No. 722717 – project OCUTHER) and ProRetina Foundation. The personnel of the animal husbandry at the Universitätsklinikums Tübingen and Norman Rieger are acknowledged for the animal care. Christine Henes is acknowledged for her skilled technical assistance with the experiments. Ellen Kilger and Sally Williamson are gratefully acknowledged for language editing and proofreading. Authors contributions: B.A.-G. designed experiments, carried out and treated organotypic cultures, performed intravitreal injections, prepared, stained, and imaged histological samples, analyzed the experimental data, and wrote the manuscript. M.S. carried out and treated organotypic cultures, prepared, stained, and imaged histological samples. M.S. and W.H. planned and carried out the ex-vivo light stimulation and activity recordings of the retinal explants. M.S. and E.M.A. performed the in silico calculations. R.G., K.H, K.Z., H.P., R.A., and. M.C. performed intravitreal injections and corresponding ERG and contributed to study planning therein. S.B. performed the EM and prepared histological samples. T.-F.C., R.D., A.U. participated in planning the study, and M.Ue. designed and coordinated the project, participated in designing the experiments, wrote the manuscript, and acquired funding for the studies. All authors have provided feedback on the results, read and approved the final manuscript. B.A.-G. and M.S. are co-first authors. B.A.-G. is listed first because she contributed more to the conception of the project and the writing of the manuscript.
Funders:
Funding AgencyGrant Number
Foundation Fighting BlindnessPPA-0717-0719-RAD
Kerstan FoundationUNSPECIFIED
Marie Curie Fellowship722717
ProRetina FoundationUNSPECIFIED
Record Number:CaltechAUTHORS:20201123-120919400
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201123-120919400
Official Citation:Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration. Blanca Arango-Gonzalez, Merve Sen, Rosellina Guarascio, Kalliopi Ziaka, Eva M. del Amo, Kwan Hau, Hannah Poultney, Rowan Asfahani, Arto Urtti, Tsui-Fen Chou, Sylvia Bolz, Raymond J. Deshaies, Wadood Haq, Michael E. Cheetham, Marius Ueffing. bioRxiv 2020.11.17.384669; doi: https://doi.org/10.1101/2020.11.17.384669
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106783
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:23 Nov 2020 20:21
Last Modified:23 Nov 2020 20:21

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