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dc.contributor.authorSzebényi, Kornélia
dc.contributor.authorWenger, Léa M. D.
dc.contributor.authorSun, Yu
dc.contributor.authorDunn, Alexander W. E.
dc.contributor.authorLimegrover, Colleen A.
dc.contributor.authorGibbons, George M.
dc.contributor.authorConci, Elena
dc.contributor.authorPaulsen, Ole
dc.contributor.authorMierau, Susanna B.
dc.contributor.authorBalmus, Gabriel
dc.contributor.authorLakatos, András
dc.date.accessioned2021-10-28T15:27:06Z
dc.date.available2021-10-28T15:27:06Z
dc.date.issued2021-10-21
dc.date.submitted2021-04-02
dc.identifier.issn1097-6256
dc.identifier.others41593-021-00923-4
dc.identifier.other923
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330002
dc.descriptionFunder: UK Dementia Research Institute
dc.description.abstractAbstract: Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating initial cellular pathologies is central to therapeutic target development, but obtaining samples from presymptomatic patients is not feasible. Here, we report the development of a cerebral organoid slice model derived from human induced pluripotent stem cells (iPSCs) that recapitulates mature cortical architecture and displays early molecular pathology of C9ORF72 ALS/FTD. Using a combination of single-cell RNA sequencing and biological assays, we reveal distinct transcriptional, proteostasis and DNA repair disturbances in astroglia and neurons. We show that astroglia display increased levels of the autophagy signaling protein P62 and that deep layer neurons accumulate dipeptide repeat protein poly(GA), DNA damage and undergo nuclear pyknosis that could be pharmacologically rescued by GSK2606414. Thus, patient-specific iPSC-derived cortical organoid slice cultures are a reproducible translational platform to investigate preclinical ALS/FTD mechanisms as well as novel therapeutic approaches.
dc.languageen
dc.publisherNature Publishing Group US
dc.subjectArticle
dc.subject/631/378/1689/1285
dc.subject/631/1647/767/1658
dc.subject/631/532/2064/2158
dc.subject/13/100
dc.subject/13/106
dc.subject/13/51
dc.subject/9/30
dc.subject/14/63
dc.subject/38/39
dc.subject/82/1
dc.subjectarticle
dc.titleHuman ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology
dc.typeArticle
dc.date.updated2021-10-28T15:26:58Z
prism.endingPage1554
prism.issueIdentifier11
prism.publicationNameNature Neuroscience
prism.startingPage1542
prism.volume24
dc.identifier.doi10.17863/CAM.77446
dcterms.dateAccepted2021-08-16
rioxxterms.versionofrecord10.1038/s41593-021-00923-4
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidSun, Yu [0000-0002-5356-3048]
dc.contributor.orcidDunn, Alexander W. E. [0000-0003-1504-499X]
dc.contributor.orcidPaulsen, Ole [0000-0002-2258-5455]
dc.contributor.orcidMierau, Susanna B. [0000-0002-1220-6423]
dc.contributor.orcidBalmus, Gabriel [0000-0003-2872-4468]
dc.contributor.orcidLakatos, András [0000-0002-1301-2292]
dc.identifier.eissn1546-1726
pubs.funder-project-idAmerican Academy of Neurology (AAN) (RG97060)
pubs.funder-project-idRCUK | Medical Research Council (MRC) (MR/P008658/1)
pubs.funder-project-idEvelyn Trust (G100774)
pubs.funder-project-idSpinal Research (G100346)


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