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It has remained an enigma why mutations in ubiquitously expressed tri\u2010snRNP proteins result in retina\u2010specific disorders, and so far, the underlying mechanism of splicing factors\u2010related RP is poorly understood.<\/jats:p><\/jats:sec>Methods<\/jats:title>We used the induced pluripotent stem cell (iPSC) technology to generate retinal organoids and RPE models from four patients with severe and very severe PRPF31\u2010adRP, unaffected individuals and a CRISPR\/Cas9 isogenic control.<\/jats:p><\/jats:sec>Results<\/jats:title>To fully assess the impacts of PRPF31<\/jats:italic> mutations, quantitative proteomics analyses of retinal organoids and RPE cells were carried out showing RNA splicing, autophagy and lysosome, unfolded protein response (UPR) and visual cycle\u2010related pathways to be significantly affected. Strikingly, the patient\u2010derived RPE and retinal cells were characterised by the presence of large amounts of cytoplasmic aggregates containing the mutant PRPF31 and misfolded, ubiquitin\u2010conjugated proteins including key visual cycle and other RP\u2010linked tri\u2010snRNP proteins, which accumulated progressively with time. The mutant PRPF31 variant was not incorporated into splicing complexes, but reduction of PRPF31 wild\u2010type levels led to tri\u2010snRNP assembly defects in Cajal bodies of PRPF31 patient retinal cells, altered morphology of nuclear speckles and reduced formation of active spliceosomes giving rise to global splicing dysregulation. Moreover, the impaired waste disposal mechanisms further exacerbated aggregate formation, and targeting these by activating the autophagy pathway using Rapamycin reduced cytoplasmic aggregates, leading to improved cell survival.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Our data demonstrate that it is the progressive aggregate accumulation that overburdens the waste disposal machinery rather than direct PRPF31\u2010initiated mis\u2010splicing, and thus relieving the RPE cells from insoluble cytoplasmic aggregates presents a novel therapeutic strategy that can be combined with gene therapy studies to fully restore RPE and retinal cell function in PRPF31\u2010adRP patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.759","type":"journal-article","created":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T03:04:51Z","timestamp":1647486291000},"source":"Crossref","is-referenced-by-count":27,"title":["Activation of autophagy reverses progressive and deleterious protein aggregation in PRPF31 patient\u2010induced pluripotent stem cell\u2010derived retinal pigment epithelium cells"],"prefix":"10.1002","volume":"12","author":[{"given":"Maria","family":"Georgiou","sequence":"first","affiliation":[{"name":"Newcastle University Biosciences Institute Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbo","family":"Yang","sequence":"additional","affiliation":[{"name":"Newcastle University Biosciences Institute Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Newcastle University Biosciences Institute Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan\u2010Ting","family":"Pan","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Multidisciplinary Sciences G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Buskin","sequence":"additional","affiliation":[{"name":"Newcastle University Biosciences Institute Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina Moya","family":"Molina","sequence":"additional","affiliation":[{"name":"Newcastle University Biosciences Institute Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Collin","sequence":"additional","affiliation":[{"name":"Newcastle University Biosciences Institute Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumana","family":"Al\u2010Aama","sequence":"additional","affiliation":[{"name":"Faculty of Medicine King Abdulaziz University Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Goertler","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian E. 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