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

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

SUBMITTER: Szebenyi K 

PROVIDER: S-EPMC8553627 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature