IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS‐associated amyotrophic lateral sclerosis

• Published in: Brain pathology (Zurich, Switzerland) Switzerland), 2024-01, Vol.34 (1), p.e13206-n/a
• Main Authors: Assoni, Amanda Faria, Guerrero, Erika N., Wardenaar, René, Oliveira, Danyllo, Bakker, Petra L., Alves, Luciana M., Carvalho, Valdemir M., Okamoto, Oswaldo Keith, Zatz, Mayana, Foijer, Floris
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Apoptosis; Cytokines; Cytoplasm; FUS gene; FUS protein; Genes; Humans; Localization; Motor neurons; Motor Neurons - metabolism; Mutation; Neurons; Nuclear transport; Oxidative Stress; Patients; Pluripotency; Point mutation; Protein biosynthesis; Protein synthesis; Proteins; RNA-Binding Protein FUS - genetics; Sarcoma; Stem cells; Translation; γ-Interferon
• ISSN: 1015-6305; 1750-3639
• DOI: 10.1111/bpa.13206

Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient‐derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUSR521H mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUSR521H MNs. Furthermore, FUSR521H MNs are more sensitive to oxidative stress and display reduced expression of TGF‐β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of FUSR521H MNs exposed to oxidative stress and partially restores the translation rates in FUSR521H MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS‐mediated protein synthesis, possibly by FUS nuclear translocation in ALS6. FUS R521H motor neurons derived from IPSCs exhibit reduced viability, decreased protein synthesis, and diminished cytokine production when exposed to oxidative stress. Treatment with IFNy improves translation rates and mitigates apoptosis caused by oxidative injury.