Highly specific ubiquitin-competing molecules as potential therapeutic tools for Friedreich’s ataxia

Friedreich’s ataxia (FRDA) is a devastating inherited neurodegenerative disease that leads to neural and cardiac degeneration associated with a progressive disability. FRDA is caused by a homozygous hyperexpansion of a GAA trinucleotide repeat in the first intron of the FTX gene, encoding the mitochondrial protein frataxin. The genetic defect results in “sticky” DNA structures and epigenetic changes that severely reduce transcription of the frataxin gene. The subsequent low levels of frataxin lead to insufficient biosynthesis of iron-sulfur clusters that are required for mitochondrial electron transport and assembly of functional aconitase, and iron dysmetabolism of the entire cell. This results in mitochondrial dysfunction and ultimately cell death, particularly in peripheral sensory ganglia. There is currently no effective treatment and patients die prematurely. Since there is an inverse correlation between the amount of residual frataxin and the severity of disease progression, therapeutic approaches aiming at increasing frataxin levels are expected to improve patients conditions. It was previously discovered by our group that a significant amount of frataxin precursor is degraded by the ubiquitin/proteasome system before its functional mitochondrial maturation. It was also provided evidence for the therapeutic potential of small molecules that increase frataxin levels by docking on the frataxin ubiquitination site, thus preventing frataxin ubiquitination and degradation. These compounds were called ubiquitin-competing molecules (UCMs). By extending the search for effective UCMs, we now identified a set of new and more potent compounds that more efficiently promote frataxin accumulation. Here I show that these compounds directly interact with frataxin and prevent its ubiquitination. Interestingly, these UCMs are not effective on the ubiquitin-resistant frataxin mutant, indicating their specific action on preventing frataxin ubiquitination. Most importantly, these compounds are able to promote frataxin accumulation and aconitase rescue in cells derived from patients, strongly supporting their therapeutic potential.