Scp160 deletion suppresses TDP-43 aggregation and toxicity in Saccharomyces cerevisiae

Protein misfolding and aggregation are central features of neurodegenerative disease, yet the cellular factors that determine whether aggregation-prone proteins become toxic remain incompletely understood. The RNA-binding protein TDP-43 forms cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS) and is toxic when expressed in yeast, providing a tractable model to identify modifiers of TDP-43 proteotoxicity. Scp160 and Bfr1 are yeast RNA-binding/translation-associated proteins linked to polysomes, ER-localized transcripts, and mRNP organization, but their contribution to TDP-43 aggregation has not been tested. Here, we expressed human TDP43-GFP in Saccharomyces cerevisiae strains lacking SCP160 or BFR1 and examined TDP43-GFP abundance, toxicity, and aggregate formation. Although deletion of SCP160 or BFR1 did not cause major changes in bulk translation, scp160Δ cells accumulated higher levels of TDP43-GFP protein, yet showed improved growth during prolonged induction and a marked reduction in severe cytoplasmic aggregates. Loss of BFR1 produced a more intermediate phenotype, reducing total aggregate-positive cells but showing a weaker effect on severe aggregates and toxicity. Thus, deletion of SCP160 uncouples TDP43-GFP abundance from toxicity and severe aggregate formation. These findings identify Scp160 and, to a lesser extent, Bfr1 as yeast factors that promote visible TDP43-GFP aggregate formation and toxicity independently of reduced protein abundance.