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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Szebényi, Kornélia 
Wenger, Léa MD 
Limegrover, Colleen A 

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.

Description

Keywords

Amyotrophic Lateral Sclerosis, Astrocytes, C9orf72 Protein, Frontotemporal Dementia, Humans, Induced Pluripotent Stem Cells, Neurons, Organ Culture Techniques, Organoids

Journal Title

Nat Neurosci

Conference Name

Journal ISSN

1097-6256
1546-1726

Volume Title

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Medical Research Council (MR/P008658/1)
Evelyn Trust (19/35)
Wellcome Trust (204845/Z/16/Z)
Wellcome Trust (204845/Z/16/Z)
Medical Research Council (2274263)
Evelyn Trust