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-β and mTORC gene pathways when stressed. Finally, we show that IFNγ 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 IFNγ response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Motor Neuron

DISEASE(S): Frontotemporal Dementia And/or Amyotrophic Lateral Sclerosis-4

SUBMITTER: AMANDA ASSONI  

LAB HEAD: Floris Foijer

PROVIDER: PXD038042 | Pride | 2024-01-26

REPOSITORIES: Pride