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FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms

ABSTRACT: Non-neuronal cells, including astrocytes, play a crucial role in the selective motor neuron pathology in amyotrophic lateral sclerosis (ALS). How astrocytes exactly contribute to the disease is not fully elucidated. Therefore, we characterised human induced pluripotent stem cell (hiPSC)-derived astrocytes from FUS-ALS patients, and incorporated these astrocytes into a human motor unit model to investigate the astrocytic effect on hiPSC-derived motor neuron network and neuromuscular junctions (NMJs). We observed a dysregulation of astrocyte homeostasis, which resulted in a FUS-ALS-mediated increase in reactivity and secretion of pro-inflammatory cytokines. Upon coculture with motor neurons and myotubes, we detected a cytotoxic effect on motor neuron-neurite morphology and outgrowth, as well as on NMJ formation and functionality, which was improved or fully rescued by isogenic control astrocytes. We conclude that mutant astrocytes have both a gain-of-toxicity and loss-of-support function in ALS, ultimately contributing to the disruption of motor neuron homeostasis, intercellular networks and NMJs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196219 | GEO | 2023/01/19

REPOSITORIES: GEO

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