IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated Amyotrophic Lateral Sclerosis

Abstract

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 ALS6 MNs. Furthermore, ALS6 MNs are more sensitive to oxidative stress and display reduced expression of TGF-{beta} and mTORC gene pathways when stressed. Finally, we show that IFN{gamma} treatment reduces apoptosis of ALS6 MNs exposed to oxidative stress and partially restores the translation rates in ALS6 MNs. Overall, these findings suggest that a functional IFN{gamma} response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6. Highlights and eTOC blurbO_LIALS6 patient-derived motor neurons show decreased viability and reduced production of innate immune cytokines following oxidative stress C_LIO_LIFUS cytoplasmic localization coincides with decreased protein synthesis rates C_LIO_LIIFN{gamma} treatment of ALS6 patient-derived motor neurons reduces apoptosis and ameliorates translation rates resulting from oxidative stress C_LI