Enhancing Proteasome Function Through NRF1 Activation: Novel Small-Molecule Compounds for Treating Neurodegenerative Diseases

Abstract

The degradation of intracellular proteins is a strictly regulated process vital formaintaining cellular homeostasis and ensuring optimal functionality of the cell. Over90% of cytosolic proteins undergo degradation via the ubiquitin-proteasome system(UPS), effectively eliminating improperly synthesized or folded proteins while alsoregulating overall protein levels and function within the cell. Any disruption in UPSactivity can induce proteotoxic stress, leading to severe pathological conditions. Onepromising strategy for addressing proteasome insufficiency involves enhancingproteasome synthesis. This can be achieved through the activation of Nuclear FactorErythroid 2-related factor 1 (NRF1), a transcription factor encoded by NFE2L1, whichtriggers the re-synthesis of proteasome genes in response to impaired proteasomefunction.