All About the Core: A Therapeutic Strategy to Prevent Protein Accumulation with Proteasome Core Particle Stimulators

The proteasome is an essential enzyme complex in cells whose main responsibility is to degrade proteins. Proteins can be degraded through either a ubiquitin-dependent or -independent mechanism by the proteasome. A variety of small molecules have been discovered that can increase the rate of protein degradation through either mechanism. However, stimulation of the ubiquitin-independent system is likely to be the most therapeutically impactful for protein-accumulation diseases. Preliminary evidence has demonstrated efficacy of this approach for reducing proteins associated with disease. To advance the field forward, validation of this mechanism in a disease model as well as more detailed studies on how much stimulation is required to achieve a therapeutic effect must be performed.