Pharmacological clearance of misfolded rhodopsin for the treatment of RHO‐associated retinitis pigmentosa
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 rhodops...
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| Veröffentlicht in: | The FASEB journal 2020-08, Vol.34 (8), p.10146-10167 |
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| creator | Liu, Xujie Feng, Bing Vats, Abhishek Tang, Hong Seibel, William Swaroop, Manju Tawa, Gregory Zheng, Wei Byrne, Leah Schurdak, Mark Chen, Yuanyuan |
| description | 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. |
| doi_str_mv | 10.1096/fj.202000282R |
| format | Article |
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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.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.202000282R</identifier><identifier>PMID: 32536017</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Cell Line ; Electroretinography - methods ; Female ; HEK293 Cells ; high‐throughput screening ; Humans ; Male ; methotrexate ; Mice ; misfolded protein degradation ; Mutant Proteins - metabolism ; Mutation - genetics ; NIH 3T3 Cells ; Photoreceptor Cells - metabolism ; Proteasome Endopeptidase Complex - metabolism ; Protein Folding ; Retina - metabolism ; Retinitis Pigmentosa - genetics ; Retinitis Pigmentosa - metabolism ; Rhodopsin - genetics ; Rhodopsin - metabolism</subject><ispartof>The FASEB journal, 2020-08, Vol.34 (8), p.10146-10167</ispartof><rights>2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology</rights><rights>2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3478-c77eecf73e9c53b5bd114cce0c5432dc3ea73db1fab531ec5d005165e754bae83</citedby><cites>FETCH-LOGICAL-c3478-c77eecf73e9c53b5bd114cce0c5432dc3ea73db1fab531ec5d005165e754bae83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.202000282R$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.202000282R$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32536017$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Xujie</creatorcontrib><creatorcontrib>Feng, Bing</creatorcontrib><creatorcontrib>Vats, Abhishek</creatorcontrib><creatorcontrib>Tang, Hong</creatorcontrib><creatorcontrib>Seibel, William</creatorcontrib><creatorcontrib>Swaroop, Manju</creatorcontrib><creatorcontrib>Tawa, Gregory</creatorcontrib><creatorcontrib>Zheng, Wei</creatorcontrib><creatorcontrib>Byrne, Leah</creatorcontrib><creatorcontrib>Schurdak, Mark</creatorcontrib><creatorcontrib>Chen, Yuanyuan</creatorcontrib><title>Pharmacological clearance of misfolded rhodopsin for the treatment of RHO‐associated retinitis pigmentosa</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>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.</description><subject>Animals</subject><subject>Cell Line</subject><subject>Electroretinography - methods</subject><subject>Female</subject><subject>HEK293 Cells</subject><subject>high‐throughput screening</subject><subject>Humans</subject><subject>Male</subject><subject>methotrexate</subject><subject>Mice</subject><subject>misfolded protein degradation</subject><subject>Mutant Proteins - metabolism</subject><subject>Mutation - genetics</subject><subject>NIH 3T3 Cells</subject><subject>Photoreceptor Cells - metabolism</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Protein Folding</subject><subject>Retina - metabolism</subject><subject>Retinitis Pigmentosa - genetics</subject><subject>Retinitis Pigmentosa - metabolism</subject><subject>Rhodopsin - genetics</subject><subject>Rhodopsin - metabolism</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp90btuFDEUBmALgcgSKGnRlDST-DK-bIMEEUmQIgUFqK0znuNdL57xYs8Spcsj5Bl5Ema0SYCGysX59B_r_IS8ZvSI0aU69psjTjmllBt-9YQsmBS0VkbRp2RBzZLXSglzQF6UspkQo0w9JweCS6Eo0wvy_fMacg8uxbQKDmLlIkKGwWGVfNWH4lPssKvyOnVpW8JQ-ZSrcY3VmBHGHodxhlfnl79u76CU5AKMs8cxDGEMpdqG1axSgZfkmYdY8NX9e0i-nX78enJeX1yefTp5f1E70WhTO60RndcCl06KVrYdY41zSJ1sBO-cQNCia5mHVgqGTnaUSqYkatm0gEYcknf73O2u7bFz0_YM0W5z6CHf2ATB_jsZwtqu0k-rlTFS6yng7X1ATj92WEY7HcJhjDBg2hXLG9bMB29mWu-py6mUjP5xDaN2Lsj6jf1T0OTf_P23R_3QyASaPbgOEW_-n2ZPv3zgnCptxG9uzKA9</recordid><startdate>202008</startdate><enddate>202008</enddate><creator>Liu, Xujie</creator><creator>Feng, Bing</creator><creator>Vats, Abhishek</creator><creator>Tang, Hong</creator><creator>Seibel, William</creator><creator>Swaroop, Manju</creator><creator>Tawa, Gregory</creator><creator>Zheng, Wei</creator><creator>Byrne, Leah</creator><creator>Schurdak, Mark</creator><creator>Chen, Yuanyuan</creator><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>202008</creationdate><title>Pharmacological clearance of misfolded rhodopsin for the treatment of RHO‐associated retinitis pigmentosa</title><author>Liu, Xujie ; Feng, Bing ; Vats, Abhishek ; Tang, Hong ; Seibel, William ; Swaroop, Manju ; Tawa, Gregory ; Zheng, Wei ; Byrne, Leah ; Schurdak, Mark ; Chen, Yuanyuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3478-c77eecf73e9c53b5bd114cce0c5432dc3ea73db1fab531ec5d005165e754bae83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Cell Line</topic><topic>Electroretinography - methods</topic><topic>Female</topic><topic>HEK293 Cells</topic><topic>high‐throughput screening</topic><topic>Humans</topic><topic>Male</topic><topic>methotrexate</topic><topic>Mice</topic><topic>misfolded protein degradation</topic><topic>Mutant Proteins - metabolism</topic><topic>Mutation - genetics</topic><topic>NIH 3T3 Cells</topic><topic>Photoreceptor Cells - metabolism</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Protein Folding</topic><topic>Retina - metabolism</topic><topic>Retinitis Pigmentosa - genetics</topic><topic>Retinitis Pigmentosa - metabolism</topic><topic>Rhodopsin - genetics</topic><topic>Rhodopsin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Xujie</creatorcontrib><creatorcontrib>Feng, Bing</creatorcontrib><creatorcontrib>Vats, Abhishek</creatorcontrib><creatorcontrib>Tang, Hong</creatorcontrib><creatorcontrib>Seibel, William</creatorcontrib><creatorcontrib>Swaroop, Manju</creatorcontrib><creatorcontrib>Tawa, Gregory</creatorcontrib><creatorcontrib>Zheng, Wei</creatorcontrib><creatorcontrib>Byrne, Leah</creatorcontrib><creatorcontrib>Schurdak, Mark</creatorcontrib><creatorcontrib>Chen, Yuanyuan</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Xujie</au><au>Feng, Bing</au><au>Vats, Abhishek</au><au>Tang, Hong</au><au>Seibel, William</au><au>Swaroop, Manju</au><au>Tawa, Gregory</au><au>Zheng, Wei</au><au>Byrne, Leah</au><au>Schurdak, Mark</au><au>Chen, Yuanyuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological clearance of misfolded rhodopsin for the treatment of RHO‐associated retinitis pigmentosa</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2020-08</date><risdate>2020</risdate><volume>34</volume><issue>8</issue><spage>10146</spage><epage>10167</epage><pages>10146-10167</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><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. 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| subjects | Animals Cell Line Electroretinography - methods Female HEK293 Cells high‐throughput screening Humans Male methotrexate Mice misfolded protein degradation Mutant Proteins - metabolism Mutation - genetics NIH 3T3 Cells Photoreceptor Cells - metabolism Proteasome Endopeptidase Complex - metabolism Protein Folding Retina - metabolism Retinitis Pigmentosa - genetics Retinitis Pigmentosa - metabolism Rhodopsin - genetics Rhodopsin - metabolism |
| title | Pharmacological clearance of misfolded rhodopsin for the treatment of RHO‐associated retinitis pigmentosa |
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