Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways

A hallmark of neurodegenerative diseases such as Parkinson’s Disease is the progressive loss of proteostasis, leading to the conversion of misfolded proteins into aggregates and subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect and degrade misfolded proteins. Here, we find that aggregation burden dictates the activation of proteasome-dependent quality control pathways. Initial misfolded proteins, enriched in oligomers, utilize UBE3C-dependent proteasomal degradation, while higher aggregation levels, enriched in larger insoluble structures, activate the NRF1 transcription factor to increase proteasome subunit transcription, and subsequent degradation capacity of cells. The role of UBE3C and NRF1 in aggregation clearance may provide therapeutic targets aimed to preventing neurodegenerative disease.