Mistranslation and ageing unmask FUS and TDP-43 toxicity in yeast models of neurodegenerative diseases

Abstract Protein aggregation is indicative of the loss of proteostasis associated with neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Proteins like Fused in sarcoma (FUS) and Tar DNA-binding protein 43 (TDP-43) accumulate and aggregate in the cytosol of neurons in ALS/FTD. Yet, it remains unclear how ageing affects FUS and TDP-43 aggregation, and how these aggregates in turn influence neurodegeneration in ALS/FTD. In addition, mistranslation can reduce longevity, challenge proteostasis, and modulate protein aggregation. To investigate how ageing and mistranslation modulate FUS and TDP-43 aggregation and toxicity, we enlist tractable and reliable yeast models. We establish that respiring yeast cells are sensitized to FUS and TDP-43 compared fermenting cells, yet this increased sensitivity does not correlate with increased FUS and TDP-43 aggregation. We also demonstrate that chronological ageing and mistranslation caused by tRNA variants antagonize FUS and TDP-43 aggregation and synergize to exacerbate FUS and TDP-43 cytotoxicity. Our work provides new insights into factors that uncouple FUS and TDP-43 aggregation from toxicity and support a rather protective role for FUS and TDP-43 aggregates in promoting longevity.