Pharmacological clearance of misfolded rhodopsin for the treatment of RHO-associated retinitis pigmentosa.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Xujie LiuYuanyuan Chen

Abstract

Rhodopsin mutation and misfolding is a common cause of autosomal dominant retinitis pigmentosa (RP). Using a luciferase reporter assay, we undertook a small-molecule high-throughput screening (HTS) of 68, 979 compounds and identified nine compounds that selectively reduced the misfolded P23H rhodopsin without an effect on the wild type (WT) rhodopsin protein. Further, we found five of these compounds, including methotrexate (MTX), promoted P23H rhodopsin degradation that also cleared out other misfolded rhodopsin mutant proteins. We showed MTX increased P23H rhodopsin degradation via the lysosomal but not the proteasomal pathway. Importantly, one intravitreal injection (IVI) of 25 pmol MTX increased electroretinogram (ERG) response and rhodopsin level in the retinae of RhoP23H/+ knock-in mice at 1 month of age. Additionally, four weekly IVIs increased the photoreceptor cell number in the retinae of RhoP23H/+ mice compared to vehicle control. Our study indicates a therapeutic potential of repurposing MTX for the treatment of rhodopsin-associated RP.

References

Sep 1, 1975·The Journal of General Physiology·F I Hárosi
Oct 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·C H SungJ Nathans
Nov 8, 1990·The New England Journal of Medicine·T P DryjaE L Berson
Apr 1, 1967·The Journal of Cell Biology·R W Young
Jun 1, 1993·Archives of Ophthalmology·E L BersonW Willett
Jan 31, 1997·Science·E M StoneV C Sheffield
Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Aug 5, 2000·Science·K PalczewskiM Miyano
Sep 27, 2000·Proceedings of the National Academy of Sciences of the United States of America·M M LaVailW W Hauswirth
Mar 10, 2001·Molecular Therapy : the Journal of the American Society of Gene Therapy·F Q LiangJ Bennett
Oct 25, 2003·Molecular Neurobiology·John H Wilson, Theodore G Wensel
Dec 21, 2004·Nucleic Acids Research·David L WheelerEugene Yaschenko
Nov 23, 2006·Lancet·Dyonne T HartongThaddeus P Dryja
Jan 18, 2007·Pflügers Archiv : European journal of physiology·Yingbin Fu, King-Wai Yau
Apr 29, 2008·The New England Journal of Medicine·Albert M MaguireJean Bennett
Apr 29, 2008·The New England Journal of Medicine·James W B BainbridgeRobin R Ali
Apr 7, 2009·Ophthalmology·Simon R J TaylorSue L Lightman
Nov 17, 2009·Journal of Molecular Biology·Mark P KrebsShalesh Kaushal
Mar 20, 2010·Advances in Experimental Medicine and Biology·Jonathan H Lin, Matthew M Lavail
Aug 13, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ryosuke MidorikawaSatoshi Goto
Aug 13, 2010·Developments in Ophthalmology·José SahelMichel Paques
Dec 21, 2011·Advances in Experimental Medicine and Biology·Hilda Petrs-SilvaWilliam W Hauswirth
Apr 5, 2012·Ophthalmology·Simon R J TaylorSue Lightman
Sep 12, 2012·Autophagy·Daniel J KlionskyBrian Zuckerbraun
Mar 22, 2013·Science Translational Medicine·Brian Y Chow, Edward S Boyden
May 30, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ekaterina S LobanovaVadim Y Arshavsky
Dec 5, 2013·Human Molecular Genetics·Mònica AguilàMichael E Cheetham
Oct 2, 2014·Molecular Neurobiology·Wei-Chieh ChiangJonathan H Lin
Feb 24, 2015·Current Opinion in Neurobiology·Ivan Tochitsky, Richard H Kramer
Mar 19, 2015·Investigative Ophthalmology & Visual Science·Yuanyuan ChenKrzysztof Palczewski
Jun 13, 2015·Investigative Ophthalmology & Visual Science·Joseph C PetersGulab S Zode

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