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To date, over 2200 ABCA4 variants have been identified, including missense, nonsense, indels, splice site and deep intronic defects. Notably, more than 60% are missense variants that can lead to protein misfolding, mistrafficking and degradation. Currently no approved therapies target ABCA4. In this study, we demonstrate that ABCA4 misfolding variants are temperature-sensitive and reduced temperature growth (30 \u00b0C) improves their traffic to the plasma membrane, suggesting the folding of these variants could be rescuable. Consequently, an in vitro platform was developed for the rapid and robust detection of ABCA4 traffic to the plasma membrane in transiently transfected cells. The system was used to assess selected candidate small molecules that were reported to improve the folding or traffic of other ABC transporters. Two candidates, 4-PBA and AICAR, were identified and validated for their ability to enhance both wild-type ABCA4 and variant trafficking to the cell surface in cell culture. We envision that this platform could serve as a primary screen for more sophisticated in vitro testing, enabling the discovery of breakthrough agents to rescue ABCA4 protein defects and mitigate ABCA4-related retinopathy.<\/jats:p>","DOI":"10.3390\/ijms25084521","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T07:44:09Z","timestamp":1713771849000},"page":"4521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Proximity Complementation Assay to Identify Small Molecules That Enhance the Traffic of ABCA4 Misfolding Variants"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5867-5383","authenticated-orcid":false,"given":"Davide","family":"Piccolo","sequence":"first","affiliation":[{"name":"UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5096-177X","authenticated-orcid":false,"given":"Christina","family":"Zarouchlioti","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3368-5221","authenticated-orcid":false,"given":"James","family":"Bellingham","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5989-2962","authenticated-orcid":false,"given":"Rosellina","family":"Guarascio","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5853-2099","authenticated-orcid":false,"given":"Kalliopi","family":"Ziaka","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4479-1831","authenticated-orcid":false,"given":"Robert S.","family":"Molday","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Cheetham","sequence":"additional","affiliation":[{"name":"UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2710","DOI":"10.1073\/pnas.1913179117","article-title":"Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases","volume":"117","author":"Hanany","year":"2020","journal-title":"Proc. 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