Small molecules affecting proteasome activity and heat shock response for clearance of toxic protein species

Abstract

The intracellular accumulation of abnormal proteins causes proteotoxic stress that leads to pathological stages. When the accumulation of redundant proteins exceeds their degradation, undesirable signaling and/or aggregation occur, which are hallmarks of neurodegenerative diseases.

This phenomenon occurs in parallel with the decline in proteasome activity. Due to the complicated structure of the 26S proteasome, its biogenesis must be strictly regulated at the levels of transcription, translation, and molecular assembly.

NRF1 (encoded by the NFE2L1 gene) is a transcription factor that upregulates the expression of all proteasome subunits in a concerted manner, especially during stress conditions. Under normal conditions, it is embedded in the membrane of the endoplasmic reticulum, retrotranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome.

However, when cell proteostasis is impaired, NRF1 is cleaved by the DDI2 protease and as a processed transcription factor, it switches on the expression of proteasome genes and other rescue factors. Therefore, activation of the NRF1 pathway could represent a new approach to delay the onset or ameliorate symptoms of neurodegenerative disorders and other disorders with disturbed proteostasis.

Here, we present a series of small compounds that are able to induce NRF1-dependent proteasome synthesis and the heat shock response both in cell lines and in C. elegans model strains. Compounds increase proteasome activity and decrease the size and number of protein aggregates.

Importantly, the compounds do not cause any cellular stress. Overall, our compounds represent a promising novel therapeutic approach for the treatment of a variety of protein conformational diseases, including the most debilitating neurodegenerative diseases.