FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration

• Published in: Cell reports (Cambridge) Vol. 42; no. 2; p. 112025
• Main Authors: Szewczyk, Barbara, Günther, René, Japtok, Julia, Frech, Moritz J., Naumann, Marcel, Lee, Hyun O., Hermann, Andreas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-02-2023; Elsevier
• Subjects: amyotrophic lateral sclerosis; CP: Neuroscience; FUS; heat stress response; integrated stress response; neurodegeneration; protein translation; proteostasis; stress granules; protein translation; FUS; CP: Neuroscience; neurodegeneration; stress granules; proteostasis; amyotrophic lateral sclerosis; heat stress response; integrated stress response
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112025

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing progressive loss of motor neurons. Mutations in Fused in sarcoma (FUS) leading to its cytoplasmic mislocalization cause a subset of ALS. Under stress, mutant FUS localizes to stress granules (SGs)—cytoplasmic condensates composed of RNA and various proteins. Aberrant dynamics of SGs is linked to the pathology of ALS. Here, using motor neurons (MNs) derived from human induced pluripotent stem cells, we show that, in mutant FUS, MN dynamics of SGs is disturbed. Additionally, heat-shock response (HSR) and integrated stress response (ISR) involved in the regulation of SGs are upregulated in mutant MNs. HSR activation correlates with the amount of cytoplasmic FUS mislocalization. While inhibition of SG formation, translation, or ISR does not influence survival of FUS ALS neurons, proteotoxicity that cannot be compensated with the activation of stress pathways is the main driver of neurodegeneration in early FUS ALS.
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•FUS ALS motor neurons show early activation of major stress response pathways•Blocking SG formation does not influence survival of neurons early in FUS ALS•Proteotoxicity is the main driver of cell death in the early stages of FUS ALS•Stress pathways preventing proteotoxicity are a rescue mechanism in early FUS ALS
Szewczyk et al. show that, in FUS ALS motor neurons, major stress response pathways are activated early, preventing proteotoxicity-driven cell death. Blocking integrated stress responses early in FUS ALS might not be beneficial. Similarly, preventing early stress granule formation is not protective in spite of signs of their aberrant dynamics.