Recently, a hexanucleotide repeat expansion (HRE) in a non-coding region of gene C9ORF72 has been identified as the most common cause of familial amyotrophic lateral sclerosis (ALS) and results in the production of five unique, highly disordered dipeptide repeat (DPR) proteins. These DPR proteins belong to a class of proteins known as intrinsically disordered proteins (IDPs) which lack a defined tertiary structure, and as a result have become known as “undruggable” targets due to the lack of binding pockets. The accumulation and aggregation of IDPs has shown to be toxic resulting in the death of neurons and has been implicated in the progression of ALS and a number of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. The 20S proteasome has shown to target IDPs for degradation to maintain protein homeostasis, however, toxic accumulation of IDPs can occur due to dysregulation of the ubiquitin-proteasome system (UPS), mutations, gene amplification, or other cellular dysregulations. Furthermore, the accumulation of these aggregation-prone IDPs has shown to lead to the formation of IDP aggregates, which are known to inhibit 20S-mediated proteolysis, resulting in the additional accumulation of toxic IDP aggregates and further disease progression. To combat the toxic accumulation of IDPs, a new therapeutic strategy has emerged using small molecules to activate the 20S proteasome, targeting IDPs through their degradation mechanism. Enhancing proteolytic activity of the 20S proteasome allows for an enhancement in the rate of IDP degradation, thereby preventing their toxic accumulation and aggregation. Current work is ongoing to explore the efficacy of 20S activators toward the newly identified DPR protein targets; we have shown 20S proteasome activation is able to enhance the degradation of DPR proteins in vitro, as well as prevent the accumulation of DPR proteins in cortical neuron cultures. Furthermore, 20S activation has shown to protect against 20S proteasome impairment caused by DPR protein aggregates and provide neuroprotection to cortical neuron cultures, suggesting this technology may offer a novel therapeutic approach for treating ALS.

Small molecule activation of the 20S proteasome prevents proteasome impairment and provides neuroprotection in presence of toxic arginine-rich C9ORF72 encoded dipeptide repeat proteins

ACS Spring 2022

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