dc.contributor.author	Szebényi, Kornélia
dc.contributor.author	Wenger, Léa M. D.
dc.contributor.author	Sun, Yu
dc.contributor.author	Dunn, Alexander W. E.
dc.contributor.author	Limegrover, Colleen A.
dc.contributor.author	Gibbons, George M.
dc.contributor.author	Conci, Elena
dc.contributor.author	Paulsen, Ole
dc.contributor.author	Mierau, Susanna B.
dc.contributor.author	Balmus, Gabriel
dc.contributor.author	Lakatos, András
dc.contributor.orcid	Sun, Yu [0000-0002-5356-3048]
dc.contributor.orcid	Dunn, Alexander W. E. [0000-0003-1504-499X]
dc.contributor.orcid	Paulsen, Ole [0000-0002-2258-5455]
dc.contributor.orcid	Mierau, Susanna B. [0000-0002-1220-6423]
dc.contributor.orcid	Balmus, Gabriel [0000-0003-2872-4468]
dc.contributor.orcid	Lakatos, András [0000-0002-1301-2292]
dc.date.accessioned	2021-10-29T15:34:14Z
dc.date.available	2021-10-29T15:34:14Z
dc.date.issued	2021-10-21
dc.date.submitted	2021-04-02
dc.date.updated	2021-10-29T15:34:05Z
dc.description	Funder: UK Dementia Research Institute
dc.description.abstract	Abstract: 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.identifier.doi	10.17863/CAM.77489
dc.identifier.eissn	1546-1726
dc.identifier.issn	1097-6256
dc.identifier.other	s41593-021-00923-4
dc.identifier.other	923
dc.identifier.uri	https://www.repository.cam.ac.uk/handle/1810/330046
dc.language	en
dc.publisher	Nature Publishing Group US
dc.subject	Article
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.subject	article
dc.title	Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology
dc.type	Article
dcterms.dateAccepted	2021-08-16
prism.endingPage	1554
prism.issueIdentifier	11
prism.publicationName	Nature Neuroscience
prism.startingPage	1542
prism.volume	24
pubs.funder-project-id	American Academy of Neurology (AAN) (RG97060)
pubs.funder-project-id	RCUK \| Medical Research Council (MRC) (MR/P008658/1)
pubs.funder-project-id	Evelyn Trust (G100774)
pubs.funder-project-id	Spinal Research (G100346)
rioxxterms.licenseref.uri	http://creativecommons.org/licenses/by/4.0/
rioxxterms.version	VoR
rioxxterms.versionofrecord	10.1038/s41593-021-00923-4

Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology

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