Retinal Organoid Single-Cell Transcriptomics Reveals Effects of PRPF31 Mutation on Early Müller Glial Activation and Progressive Photoreceptor Degeneration

Retinal Organoid Single-Cell Transcriptomics Reveals Effects of PRPF31 Mutation on Early Müller Glial Activation and Progressive Photoreceptor Degeneration | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Retinal Organoid Single-Cell Transcriptomics Reveals Effects of PRPF31 Mutation on Early Müller Glial Activation and Progressive Photoreceptor Degeneration Alessandro Bellapianta, Jingjing Qi, Michele Giugliano, Sara Ouaidat, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6923352/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Dec, 2025 Read the published version in Biomedicines → Version 2 posted You are reading this latest preprint version Show more versions Abstract Retinitis pigmentosa (RP) encompasses a group of inherited retinal disorders characterized by progressive degeneration of rod and cone photoreceptors, leading to vision loss. Among RP subtypes, RP11 is linked to mutations in PRPF31, a key spliceosome component, resulting in retinal cell dysfunction. Although PRPF31 is ubiquitously expressed, its mutations predominantly impact retinal cells, leading to the progressive loss of photoreceptors. Despite significant progress, studies focused on photoreceptor and retinal pigment epithelium dysfunction in late disease stages, leaving early molecular events and the involvement of other retinal cell types unresolved. Moreover, comprehensive single-cell analyses capturing dynamic transcriptional changes across all retinal populations at early and late differentiation stages are still lacking. Using patient-derived Retinal Organoids (ROs), this study investigates the developmental trajectory of PRPF31-RP11 mutation through a series of morphological, functional, molecular and transcriptomics analysis. Our results show that ROs recapitulate in vitro key features of RP, including photoreceptor loss and functional impairment. Single-cell RNA sequencing revealed early Müller glial expansion, retinal ganglion cell stress, and progressive photoreceptor degeneration. Findings identify dysregulated molecular pathways associated with phototransduction, oxidative stress, and inflammation, providing insights into RP11 pathogenesis and potential therapeutic targets. Ophthalmology Cellular & Molecular Neuroscience Molecular Biology Stem Cell & Developmental Cell Biology PRPF31 Retinitis Pigmentosa Retinal Dystrophies Retinal Organoids induced pluripotent stem cells single-cell RNA sequencing Müller glia Photoreceptor degeneration Retinal Ganglion Cells Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryDatav1AB.docx Supplementary data Cite Share Download PDF Status: Published Journal Publication published 23 Dec, 2025 Read the published version in Biomedicines → Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6923352","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":479423516,"identity":"07f14620-4970-479c-af0b-719ff8c7ce1f","order_by":0,"name":"Alessandro Bellapianta","email":"","orcid":"","institution":"Johannes Kepler University Linz, Kepler University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Bellapianta","suffix":""},{"id":479423517,"identity":"e7c02a89-c432-4901-b432-e7b13682af97","order_by":1,"name":"Jingjing Qi","email":"","orcid":"","institution":"Johannes Kepler 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Activation and Progressive Photoreceptor Degeneration\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PRPF31, Retinitis Pigmentosa, Retinal Dystrophies, Retinal Organoids, induced pluripotent stem cells, single-cell RNA sequencing, Müller glia, Photoreceptor degeneration, Retinal Ganglion Cells","lastPublishedDoi":"10.21203/rs.3.rs-6923352/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6923352/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRetinitis pigmentosa (RP) encompasses a group of inherited retinal disorders characterized by progressive degeneration of rod and cone photoreceptors, leading to vision loss. Among RP subtypes, RP11 is linked to mutations in PRPF31, a key spliceosome component, resulting in retinal cell dysfunction. Although PRPF31 is ubiquitously expressed, its mutations predominantly impact retinal cells, leading to the progressive loss of photoreceptors. Despite significant progress, studies focused on photoreceptor and retinal pigment epithelium dysfunction in late disease stages, leaving early molecular events and the involvement of other retinal cell types unresolved. Moreover, comprehensive single-cell analyses capturing dynamic transcriptional changes across all retinal populations at early and late differentiation stages are still lacking. Using patient-derived Retinal Organoids (ROs), this study investigates the developmental trajectory of PRPF31-RP11 mutation through a series of morphological, functional, molecular and transcriptomics analysis. Our results show that ROs recapitulate in vitro key features of RP, including photoreceptor loss and functional impairment. Single-cell RNA sequencing revealed early Müller glial expansion, retinal ganglion cell stress, and progressive photoreceptor degeneration. Findings identify dysregulated molecular pathways associated with phototransduction, oxidative stress, and inflammation, providing insights into RP11 pathogenesis and potential therapeutic targets.\u003c/p\u003e","manuscriptTitle":"Retinal Organoid Single-Cell Transcriptomics Reveals Effects of PRPF31 Mutation on Early Müller Glial Activation and Progressive Photoreceptor Degeneration","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-10-02 17:39:18","doi":"10.21203/rs.3.rs-6923352/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2025-07-02 06:45:24","doi":"10.21203/rs.3.rs-6923352/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"71209888-6a71-4e48-95c5-0bf1c38ca6c1","owner":[],"postedDate":"October 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":55684938,"name":"Ophthalmology"},{"id":55684939,"name":"Cellular \u0026 Molecular Neuroscience"},{"id":55684940,"name":"Molecular Biology"},{"id":55684941,"name":"Stem Cell \u0026 Developmental Cell Biology"}],"tags":[],"updatedAt":"2026-01-07T14:48:40+00:00","versionOfRecord":{"articleIdentity":"rs-6923352","link":"https://doi.org/10.3390/biomedicines14010045","journal":{"identity":"biomedicines","isVorOnly":true,"title":"Biomedicines"},"publishedOn":"2025-12-24 00:00:00","publishedOnDateReadable":"December 24th, 2025"},"versionCreatedAt":"2025-10-02 17:39:18","video":"","vorDoi":"10.3390/biomedicines14010045","vorDoiUrl":"https://doi.org/10.3390/biomedicines14010045","workflowStages":[]},"version":"v2","identity":"rs-6923352","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6923352","identity":"rs-6923352","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}