Discovery of Small Molecule Activators of NRF1 Transcriptional Activity Preventing Protein Aggregation

Abstract

The intracellular accumulation of abnormal proteins exceeding their degradation can cause imbalance in proteostasis resulting in proteotoxic stress that leads to severe pathological stages. This state relates to proteasome saturation/ insufficiency which requires upregulation of proteasome subunits. Nuclear Factor Erythroid 2-related factor 1 (NRF1) is a transcription factor (encoded by NFE2L1) which activates proteasome gene re-synthesis upon impairment of the proteasome function. Therefore, targeted activation of the NRF1 pathway could represent a new approach to delay the onset neurodegenerative diseases and other disorders with disturbed proteostasis.