Discovery of the activators of NRF1 pathway affecting proteasome activity and preventing protein aggregation

Abstract

Neurodegenerative disorders (NDs) are one of the most devastating diseases of our time for which there is no cure. A hallmark event in neurodegeneration is the misfolding, aggregation, and accumulation of abnormal proteins, causing proteotoxic stress that leads to pathological stages.

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 condition NRF1 is degraded by the proteasome.

However, when cell proteostasis is disturbed 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 improve symptoms of neurodegenerative disorders and other disorders with disturbed proteostasis.

Here, we present a series of 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. These compounds increase proteasome activity, decrease the number and the size of protein aggregates and importantly, they do not cause any cellular stress.

Overall, preventing of protein aggregation by increasing the capacity of protein degradation machineries by using our compounds represents a promising novel therapeutic strategy for neurodegenerative diseases and proteinopathies in general.