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

Protein misfolding and aberrant protein aggregation are central features of neurodegenerative disorders, including amyotrophic lateral sclerosis, where the RNA-binding protein TDP-43 accumulates in abnormal intracellular assemblies. Although yeast models have identified multiple modifiers of TDP-43 toxicity, the cellular factors that determine how aggregation-prone proteins are organized remain incompletely understood. Here, we investigated whether the ribosome- and mRNP-associated proteins Scp160 and Bfr1 influence TDP-43 proteotoxicity and aggregate formation. We report that deletion of SCP160 or BFR1 improves growth during TDP43-GFP induction without reducing steady-state reporter abundance and decreases formation of prominent TDP43-GFP foci. Deletion of BFR1 produced an intermediate TDP-43 phenotype, with a weaker effect than SCP160 deletion on severe foci formation and toxicity. Importantly, the effect of SCP160 or BFR1 deletion on visible protein aggregation was not specific to TDP-43: severe Htt103Q-GFP aggregation was strongly reduced, and formation of VHL-GFP foci was suppressed, including under conditions of proteasome inhibition. Despite these shared effects, the two mutants were not phenotypically identical. Deletion of SCP160 produced a distinct spatial phenotype in which residual TDP43-GFP foci showed markedly increased association with Sec63-positive ER structures and reduced distance to these regions, whereas bfr1 Δ cells did not show the same Sec63-associated shift. Together, these findings uncouple TDP43-GFP abundance from toxicity and prominent foci formation and identify Scp160 and Bfr1 as factors that influence the intracellular partitioning of aggregation-prone and misfolded proteins, with an additional role for Scp160 in the spatial organization of TDP43 relative to the ER.