Mini brains to study motor neuron disease and frontotemporal dementia
October 2021
University of Cambridge, Cambridge, United Kingdom
Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating the initial cellular pathologies is central to developing therapeutic targets, but it is not possible to obtain samples from presymptomatic patients. Here, the researchers develop a long-term human cortical organoid (CO) model that accurately recapitulates the early molecular pathology of ALS/FTD. COs were grown from iPSCs derived from patients with ALS/FTD carrying the C9ORF72 mutation (C9 ALI-COs). This mutation is useful for modelling ALS/FTD as it causes a variety of pathologies in both sporadic and inherited forms of the disease. Using ALI-CO discs cultured from the organoids, ALI-COs are shown to form consistent microarchitecture and disease-relevant phenotypes. Furthermore, it was found that C9 ALI-COs, although lacking microglia and vasculature, exhibit astroglia- and neuron-specific perturbations. These results demonstrate that hiPSC-derived ALI-COs provide a reproducible platform with the necessary longevity and maturity to study ALS/FTD, thereby revealing early and targeted cellular vulnerabilities relevant to presymptomatic clinical stages.
Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology
András Lakatos, Gabriel Balmus
Added on: 11-09-2021
[1] https://www.nature.com/articles/s41593-021-00923-4
