Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology.
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
02
04
2021
accepted:
16
08
2021
pubmed:
23
10
2021
medline:
11
11
2021
entrez:
22
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34675437
doi: 10.1038/s41593-021-00923-4
pii: 10.1038/s41593-021-00923-4
pmc: PMC8553627
doi:
Substances chimiques
C9orf72 Protein
0
C9orf72 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1542-1554Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P008658/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 204845/Z/16/Z
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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